Review

Correspondence *Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

Email young.william@mayo.edu

Introduction

The prevalence of hypertension has increased over the past several decades. It is estimated that approximately 85 million people (28.7% of total population) in the US are currently hypertensive.¹ Although most cases of hypertension are 'essential' or 'idiopathic', some cases have an identifiable cause, secondary hypertension. Identifying this latter subgroup is important as patients can be offered a curative therapy or targeted pharmacotherapy. The most common form of secondary hypertension is primary aldosteronism. Defined as hypertension associated with low renin and increased aldosterone levels that are not suppressed by appropriate testing (see below), primary aldosteronism was first described by Conn in 1955 in a 34-year-old woman with hypertension, intermittent paralysis, hypokalemia and metabolic alkalosis.² Further biochemical analyses detected increased activity of urinary salt-retaining corticoid. The patient was cured by removal of a benign adrenal adenoma.³

Conn initially suggested that primary aldosteronism might affect up to 20% of hypertensive patients, but later revised his estimate to 10%.⁴ During the ensuing decades the prevalence of primary aldosteronism among hypertensive patients was found to be less than 3.5%.^{5, 6, 7, 8, 9, 10} In 1976, measurement of the ratio of plasma aldosterone concentration (PAC) to plasma renin activity (PRA) was introduced as a test to screen for primary aldosteronism¹¹ but was not used routinely until the early 1980s when Hiramatsu and colleagues proposed it be the first-line case-finding test for the condition.¹² Use of the PAC : PRA ratio has substantially increased the number of confirmed cases of primary aldosteronism worldwide.¹³ Clinical investigators have found the prevalence of primary aldosteronism among nonselected hypertensive persons to be between 5% and 13%.^{14, 15, 16, 17, 18, 19, 20} So, with an estimated prevalence of 10%, approximately 8.5 million people in the US have primary aldosteronism.

The prevalence of primary aldosteronism increases with severity of hypertension. Mosso and colleagues¹⁴ showed that prevalence was 1.99% in subjects with STAGE 1 HYPERTENSION (according to the Joint National Committee 6); 8.02% in STAGE 2 HYPERTENSION; and 13.2% in STAGE 3 HYPERTENSION. Among patients with resistant hypertension, the prevalence of primary aldosteronism has been reported to be 17–20%.^{21, 22} African American and black South African subjects have lower renin levels than Caucasian subjects;^{23, 24} this could influence the result of the PAC : PRA ratio test, but ethnic differences have not been found to affect the prevalence of primary aldosteronism.²¹ Consistent age effects are not evident. Compared with essential hypertension, primary aldosteronism has been reported by some to be more common among younger patients; others have detected no difference between age-groups.^{14, 16, 21} No difference between the sexes has been reported.¹⁴

Pathogenesis

Aldosterone, produced in the ZONA GLOMERULOSA, is synthesized and released mainly in response to renin-dependent production of ANGIOTENSIN II; however, adrenocorticotropic hormone (ACTH), serum potassium, and dopamine also affect its production and secretion. Aldosterone exerts its effect by binding to the nuclear mineralocorticoid receptor. This ligand–receptor complex attaches to DNA and promotes gene expression. In epithelial tissues (e.g. renal tubular cells, distal colon and salivary glands) aldosterone enhances uptake of sodium; water follows, resulting in increased volume load and cardiac output. Sodium reabsorption is accompanied by potassium excretion. In the past, hypokalemia was thought to be a mandatory finding in primary aldosteronism but, as noted by Conn and colleagues in 1965,²⁵ the potassium levels in primary aldosteronism need not be below normal. Later studies confirmed that most patients with primary aldosteronism are normokalemic.^{13, 14, 15, 16, 17, 21, 26, 27}

In addition to causing hypertension, high levels of aldosterone have negative effects on nonepithelial tissues. These include increased oxidative stress and collagen remodeling, which result in endothelial dysfunction, left ventricular hypertrophy and fibrosis in the kidney, heart and blood vessels.²⁸ Both animal experiments and in vitro studies have shown that these effects are independent of hypertension. For example, long-term administration of aldosterone to rats increases collagen formation in both the right and left cardiac ventricles²⁹ and induces coronary inflammation with focal ischemic lesions.³⁰ Blockade of the mineralocorticoid receptor (which only partially normalizes blood pressure) substantially ameliorates the inflammatory reaction.³⁰ It has been suggested that left ventricular hypertrophy is a result of high sodium intake inducing a local increase in aldosterone synthase within myocardial cells.³¹ It is clear, however, that PAC has a role; there is a positive correlation between cardiac collagen content (measured by ultrasonic backscatter) and plasma aldosterone levels in humans.³²

The negative effect of circulating aldosterone on cardiac function was documented recently by Stowasser and colleagues.³³ These authors reported that in young, nonhypertensive subjects with glucocorticoid-remediable aldosteronism, left ventricular wall thickness is increased and diastolic function is reduced compared with age- and sex-matched controls. Indeed, cardiovascular events (stroke, myocardial infarction and atrial fibrillation) are more common in patients with primary aldosteronism than in subjects with essential hypertension, a finding that is independent of blood pressure.³⁴ Clinical multicenter studies (Randomized Aldactone Evaluation Study [RALES] and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study [EPHESUS]) have shown that addition of a mineralocorticoid receptor antagonist to treatment regimens decreases morbidity and mortality among patients with cardiovascular diseases.^{35, 36}

Aldosterone excess might also exert effects beyond blood pressure and the cardiovascular system. Although its pathogenesis is unclear, the metabolic syndrome is more common among patients with primary aldosteronism than among patients with essential hypertension.³⁷ Experimentally, aldosterone excess has been linked with bone loss due to concomitant increases in urinary calcium and magnesium excretion.³⁸

Subtypes

The relative frequencies of the different forms of primary aldosteronism are listed in Table 1. The two major subtypes are bilateral idiopathic hyperaldosteronism (IHA) and aldosterone-producing adenoma (APA; Figure 1). As most patients with primary aldosteronism are normokalemic and the PAC : PRA ratio is increasingly being used as a case-finding test, IHA is now the most frequently diagnosed subtype.^{18, 39} In general, IHA patients are older, have milder hypertension and are more frequently normokalemic than those with APA.⁴⁰ Unilateral adrenal hyperplasia is an unusual subtype. Nonetheless, this diagnosis should be considered when adrenal vein sampling shows lateralization but an APA is not detected during histological examination.⁴¹ Approximately 1% of patients with primary aldosteronism are shown to have an aldosterone-producing adrenocortical carcinoma. In a summary based on 58 case reports, Seccia and colleagues found that mean survival time was approximately 1.5 years. There was wide variation in tumor size. In less than half of the patients who had undergone preoperative CT, the imaging findings were indicative of malignancy (e.g. heterogeneous density, calcification).⁴²

Figure 1 CT of a right adrenal mass in a 35-year-old woman with a 7-year history of hypertension.

(A) Axial image showing 2-cm right adrenal nodule (arrow), Hounsfield unit score 8. (B) Coronal image. As adrenal venous sampling performed at a local hospital was not conclusive, the patient was referred to Mayo Clinic (Rochester, MN) for a second opinion. Laboratory study results included the following: serum potassium, 3.3 mEq/l (3.3 mmol/l [during replacement with potassium chloride 96 mEq daily]); plasma aldosterone concentration (PAC), 46 ng/dl (1,276 pmol/l); and plasma renin activity, <0.6 ng/dl per hour. Repeat adrenal venous sampling showed that right adrenal vein PAC was 19,795 ng/dl (549,113 pmol/l [right adrenal vein PAC : plasma cortisol ratio, 19.8]); left adrenal vein PAC was 543 ng/dl (15,062 pmol/l [left adrenal vein PAC : plasma cortisol ratio, 0.71]); and inferior vena cava PAC was 104 ng/dl (2,885 pmol/l [inferior vena cava PAC : plasma cortisol ratio, 4.5]). The right-to-left lateralization ratio was 27.9:1.0 (right PAC : cortisol divided by left PAC : cortisol) and consistent with a right aldosterone-producing adenoma. Laparoscopic right adrenalectomy was recommended.

Full figure and legend (88K)Figures & Tables indexDownload Power Point slide (210K)

Table 1 Subtypes of primary aldosteronism. Adapted from reference 45.

Full tableFigures & Tables indexDownload Power Point slide (124K)

Familial forms of primary aldosteronism include familial hyperaldosteronism type 1 (FH-1) or glucocorticoid-remediable aldosteronism (GRA), and FH-2 (familial occurrence of APA, IHA or both). GRA, which is inherited in an autosomal dominant fashion, is caused by recombination between CYP11B1 and CYP11B2, which encode members of the cytochrome P450 superfamily of enzymes. The chimeric gene formed via recombination has aldosterone synthase activity. It is expressed throughout the adrenal cortex and regulated primarily by ACTH.⁴³ In addition to increased PAC, levels of 18-OH-cortisol and 18-oxo-cortisol are increased in GRA. Severity of hypertension is associated with gender and with the position at which the genes cross over. FH-2 occurs more frequently than GRA, and familial studies indicate autosomal dominant inheritance. In some families, FH-2 is linked to a mutation in the 7p22 region. Such a linkage has not been found in other families, indicating that FH-2 is a genetically heterogeneous disease.⁴⁴

Case finding

Testing for primary aldosteronism should be considered in any of the following circumstances: (i) hypertension and spontaneous hypokalemia or hypokalemia provoked by administration of a low-dose diuretic; (ii) severe hypertension (i.e. Joint National Committee 7 stage 2 hypertension, 160 mmHg systolic and/or 100 mmHg diastolic; (iii) a patient requires three or more antihypertensive drugs; (iv) hypertension manifests at a young age (e.g. <20 years); (v) adrenal incidentaloma is present; (vi) whenever an evaluation for secondary hypertension is considered (e.g. when testing for renovascular disease or PHEOCHROMOCYTOMA); and (vii) hypertensive relatives of patients with primary aldosteronism.

Ratio of plasma aldosterone concentration to plasma renin activity

After correcting hypokalemia (if present), the blood of patients who are likely to have primary aldosteronism should be sampled for measurement of PAC and PRA, and the PAC : PRA ratio should be calculated. As a clinical guideline, a PAC : PRA ratio 20 ng/dl per ng/ml per hour (554 pmol/l per ng/ml per hour) in combination with a PAC 15 ng/dl (416 pmol/l) in a morning blood sample from an ambulant patient is indicative of primary aldosteronism. Confirmatory testing (see section below) should be performed. It is important to note that the PAC : PRA ratio threshold is laboratory-dependent. Mineralocorticoid receptor antagonists (spironolactone and eplerenone) and high-dose amiloride (e.g. >5 mg daily) should be discontinued 6 weeks before blood sampling to avoid direct interference with the results. Blood pressure and serum potassium levels need to be monitored closely during drug withdrawal.^{39, 45} An algorithm of case findings and further evaluation is presented in Figure 2.

Figure 2 Algorithm for using the ratio of plasma aldosterone concentration to plasma renin activity as a case-finding tool, and for subtype evaluation, of primary aldosteronism.

This algorithm should be modified on the basis of clinical circumstance; common sense should prevail.

AVS, adrenal vein sampling; HU, Hounsfield units; PAC, plasma aldosterone concentration; PRA, plasma renin activity.

Full figure and legend (53K)Figures & Tables indexDownload Power Point slide (125K)

The use of the PAC : PRA ratio has been questioned because it is primarily an indicator of low renin levels⁴⁶ and might be affected by patient age, ethnicity, -adrenergic blockers, angiotensin-receptor blockers, calcium-channel blockers, angiotensin-converting-enzyme inhibitors, posture and diurnal hormone cycles.^{26, 47, 48} When the effects of the antihypertensive drugs atenolol, amlodipine, doxazosin, fosinopril and irbesartan on the PAC : PRA ratio were investigated in a group of patients with suspected primary aldosteronism, amlodipine and irbesartan were shown to contribute to a false-negative ratio.²⁶ In a recent study of 118 subjects with essential hypertension, Schwartz and Turner¹⁹ showed that neither antihypertensive medications nor acute variation of dietary sodium adversely affected the accuracy of the PAC : PRA ratio. Sensitivity of the ratio during periods with and without therapy was 73% and 87%, respectively; specificity was 74% and 75%, respectively. Furosemide and upright posture do not improve the post-test probability of APA to a greater extent than using the baseline PAC : PRA ratio.⁴⁹ It is important to recognize, however, that the PAC : PRA ratio is only a screening test. A confirmatory aldosterone suppression test must be conducted to verify autonomous aldosterone production before treatment is initiated.

In a systematic review of 16 studies (3,136 total participants) Montori and Young⁵⁰ found that the threshold PAC : PRA ratios used varied between 7.2 and 100.0 ng/dl per ng/ml per hour (200 and 2,774 pmol/l per ng/ml per hour). Sensitivity and specificity for APA varied between 64% and 100%, and 87% and 100%, respectively. Descriptions of reference standards and attribution of diagnosis at the end of the studies were, however, incomplete. In addition, origin of the study cohort, ongoing antihypertensive medications, use of high versus low salt diet, and circumstances during blood sampling were not standardized. The authors concluded that none of the studies provided valid estimates of PAC : PRA ratio test characteristics (sensitivity, specificity and likelihood ratio at different cutoff levels).

In a retrospective study of 62 patients (45 with primary aldosteronism and 17 with essential hypertension), Tiu and colleagues⁵¹ showed that the PAC : PRA ratio has a larger area under the RECEIVER OPERATING CHARACTERISTIC CURVE than PAC or PRA alone, thus justifying the use of the PAC : PRA ratio as a first-line case-finding test. The cutoff levels corresponding to the highest accuracy for the PAC : PRA ratio varied with posture and time of day, and this test should be standardized both within and between centers to minimize variability. Adding PAC as a single variable to the PAC : PRA ratio provides a higher sensitivity and specificity for identifying primary aldosteronism.⁵²

Confirmatory testing

The most widely used confirmatory tests for primary aldosteronism are intravenous saline loading, oral sodium loading and the fludrocortisone suppression test (FST). The principle underlying these tests is that an increase in intravascular volume should decrease renin release and subsequent aldosterone production in patients without primary aldosteronism. Sodium suppression testing is performed by one of two methods. First, oral administration of sodium chloride (12 g per day for 4 days) and measurement of urinary aldosterone level and sodium excretion on days 3 to 4 (normal suppression is defined as a 24-h urinary aldosterone concentration <12 g, concomitant with urinary sodium >200 mmol/day). Some patients already consume a diet with such high sodium content that administration of sodium chloride tablets is unnecessary. The second technique is intravenous infusion of 2 l of normal saline over 4 h, and measurement of PAC at baseline and 4-h time points (normal suppression is defined as PAC <10 ng/dl [277 pmol/l]). Intravenous sodium loading should start during the morning, as the circadian rhythm of ACTH will lower PAC in some patients with adenoma and GRA, thereby generating false-negative results.

In the FST, fludrocortisone acetate is administered for 4 days (0.1 mg every 6 h) concomitant with a high sodium diet and slow-release sodium chloride 30 mmol (1.8 g) three times per day. Plasma potassium level should be measured daily and the patient given sufficient supplements to maintain normal levels. Failure to suppress upright PAC (measured at 10:00 h) to a level less than 6 ng/dl (166 pmol/l) at day 4 is diagnostic of primary aldosteronism, provided that PRA is <1 ng/ml/h, serum cortisol concentration is less at 10:00 h than at 07:00 h, and plasma potassium is within normal range.⁵⁶ It should be noted that increased QT DISPERSION in combination with deterioration of ventricular function has been reported during the FST.⁵⁷ For this reason, this test should be used with care, and the authors do not recommend it as a first choice.

The captopril suppression test (CST) has also been introduced as a potential confirmatory technique for primary aldosteronism. Captopril inhibits the conversion of angiotensin I to angiotensin II, thereby inhibiting aldosterone production and increasing renin levels in healthy subjects. CST is performed by measuring plasma aldosterone levels before and 2 h after oral administration of 25 mg captopril. Normal suppression is defined as PAC less than 15 ng/dl (416 pmol/l) and a PAC : PRA ratio less than 50 ng/dl per ng/ml per hour (1,387 pmol/l per ng/ml per hour).⁵⁸ In a comparative study of CST and oral salt loading in 49 subjects, Agharazii and colleagues⁵⁹ detected comparable sensitivity. The authors noted that because the CST did not depend on sodium intake, it could be performed in patients for whom salt loading is contraindicated (such as those with cardiac failure) and is an efficient alternative test. Additional confirmatory studies and a better assessment of test characteristics are needed before the CST can be recommended as a replacement for the current standard confirmatory tests. It should also be noted that administration of captopril can result in profound hypotension in some patients. Careful blood pressure monitoring is required.

It should be noted that all of the confirmatory tests mentioned above have risks and should be used with care in patents with compromised left ventricular cardiac function.

Subtype evaluation

As treatment options differ for different forms of primary aldosteronism, it is important to determine the disease subtype. After the diagnosis of primary aldosteronism has been confirmed, the patient should undergo CT (with or without contrast enhancement) with 2–3-mm thick slices of the adrenal glands. The probability of identifying an adrenal mass on CT is approximately 6%;⁶⁰ however, most adrenal nodules found on CT are nonfunctional and benign.⁶¹ As such, the anatomic identification of an adrenal mass on CT in a patient with primary aldosteronism does not establish a cause-and-effect relationship. Of 203 patients who underwent both CT and adrenal vein sampling (AVS), 51% of those with a unilateral micronodule (1 cm) produced aldosterone at the contralateral side and 41% of those producing aldosterone unilaterally had normal CT findings.⁶² So, adrenal CT lacks the overall accuracy to distinguish between unilateral and bilateral disease.

When the patient and clinician wish to pursue surgical treatment (see section below), AVS should also be performed in most patients. AVS is technically difficult and requires a radiologist with experience. A subtype study that clinicians can use is [iodine-131]6--iodomethyl-19-norcholesterol (NP-59) scintigraphy. Although advocated by some groups,⁶³ the sensitivity of NP-59 scintigraphy depends heavily on the size of the adenoma.^{64, 65} Because tracer uptake was poor in adenomas less than 1.5 cm in diameter, this method was not often helpful in interpreting micronodular findings obtained with high-resolution CT. In addition to its poor sensitivity, other reasons that NP-59 is rarely used in the US include the following: (i) NP-59 is not approved by the FDA, and its use requires institutional review board approval; (ii) dexamethasone is administered at 1 mg every 6 h starting 7 days before NP-59 injection and continued throughout the scanning period; (iii) imaging starts on day 4 after NP-59 injection, and can continue daily through day 10; (iv) a lateralizing scan can be seen in adrenal cortical adenomas that do not secrete aldosterone; and (v) only three or four centers in the US currently offer NP-59 scintigraphy.

On CT, benign cortical adenomas are uniform, round and hypodense (e.g. Hounsfield unit score 10).⁶⁶ So, for cases in which APA is highly likely (patients 40 years of age with marked primary aldosteronism, e.g. PAC 30 ng/dl [832 pmol/l]) and a well-defined, hypodense adrenal mass (>1 cm on CT scan) is identified, AVS can be bypassed and the patient can undergo unilateral laparoscopic adrenalectomy.^{39, 67} A review by Kloos et al. included discussion of age-dependent prevalence of adrenal cortical adenomas. In patients with primary aldosteronism, the likelihood that an adrenal mass is related to the primary aldosteronism is much greater in a 20-year-old than in a 70-year-old; in the latter patient group, the prevalence of clinically nonfunctioning cortical adenomas exceeds 7%.⁶¹ So, when CT shows a unilateral nodule in a patient who is older than 40 years, the physician should not assume that the mass is the source of excess aldosterone. Finding an irregular adrenal mass or a dense adrenal mass (Hounsfield unit score >10 detected by adrenal CT) in a patient with primary aldosteronism is not typical of a benign aldosterone-producing adenoma; the adrenal mass might not be the source of aldosterone hypersecretion. When large adrenal masses (>4 cm) that are dense or have mixed attenuation on CT are found in patients with primary aldosteronism, a diagnosis of adrenocortical carcinoma should be considered. If surgical treatment is to be pursued in this clinical setting, then AVS is mandatory. In 101 patients with AVS-predicted and surgically confirmed solitary APA at the Mayo Clinic, Rochester, no significant correlation was found between PAC and tumor size (Figure 3).

Figure 3 Relationship between maximal diameter of aldosterone-producing adenoma at pathology examination and plasma aldosterone concentration (n = 101).

Only subjects with adrenal vein sampling-predicted and surgically confirmed solitary unilateral aldosterone-producing adenoma were included. r_s, Spearman rank correlation coefficient.

Full figure and legend (21K)Figures & Tables indexDownload Power Point slide (107K)

Cerebrovascular complications at a young age can affect up to 18% of patients with GRA.⁶⁸ As such, patients with primary aldosteronism who have early-onset hypertension (i.e. before the age of 20 years), a family history of primary aldosteronism or a family history of stroke (<40 years of age) should undergo screening tests for GRA. Because aldosterone production is ACTH-dependent, the dexamethasone suppression test can be used in the diagnostic work-up, although germline mutation testing is the best single test.⁶⁹ In clinical practice, FH-2 is indistinguishable from APA and IHA, and the diagnosis can be made only by documenting primary aldosteronism in other family members and excluding GRA with genetic testing.

Treatment

Conclusion

Primary aldosteronism is a common and potentially curable cause of hypertension. Measurement of the PAC : PRA ratio and PAC are inexpensive, low-risk case-finding tools that are available at most medical centers. Optimal treatment (from both individual and cost-effective perspectives) for APA is unilateral laparoscopic adrenalectomy. All pharmacologically managed patients should receive a mineralocorticoid receptor antagonist to prevent the negative effects of aldosterone on nonepithelial tissues.

References

1. Hajjar I and Kotchen TA (2003) Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. JAMA 290: 199–206 | Article | PubMed | ISI |
2. Conn JW (1955) Presidental address: part I painting background; part II primary aldosteronism, a new clinical syndrome. J Lab Clin Med 45: 3–17 | PubMed | ISI | ChemPort |
3. Conn JW and Conn ES (1961) Primary aldosteronism versus hypertensive disease with secondary aldosteronism. Recent Prog Horm Res 17: 389–414 | PubMed | ISI | ChemPort |
4. Conn JW (1966) The evolution of primary aldosteronism: 1954–1967. Harvey Lect 62: 257–291 | PubMed |
5. Andersen GS et al. (1988) The incidence rate of phaeochromocytoma and Conn's syndrome in Denmark, 1977–1981. J Hum Hypertens 2: 187–189 | PubMed | ISI | ChemPort |
6. Berglund G et al. (1976) Prevalence of primary and secondary hypertension: studies in a random population sample. Br Med J 2: 554–556 | PubMed | ISI | ChemPort |
7. Fishman LM et al. (1968) Incidence of primary aldosteronism uncomplicated "essential" hypertension: a prospective study with elevated aldosterone secretion and suppressed plasma renin activity used as diagnostic criteria. JAMA 205: 497–502 | Article | PubMed | ChemPort |
8. Streeten DH et al. (1979) Reliability of screening methods for the diagnosis of primary aldosteronism. Am J Med 67: 403–413 | Article | PubMed | ISI | ChemPort |
9. Tucker RM and Labarthe DR (1977) Frequency of surgical treatment for hypertension in adults at the Mayo Clinic from 1973 through 1975. Mayo Clin Proc 52: 549–545 | PubMed | ISI | ChemPort |
10. Kaplan NM (1967) Hypokalemia in the hypertensive patient, with observations on the incidence of primary aldosteronism. Ann Intern Med 66: 1079–1090 | PubMed | ISI | ChemPort |
11. Dunn PJ and Espiner EA (1976) Outpatient screening tests for primary aldosteronism. Aust NZ J Med 6: 131–135 | ChemPort |
12. Hiramatsu K et al. (1981) A screening test to identify aldosterone-producing adenoma by measuring plasma renin activity: results in hypertensive patients. Arch Intern Med 141: 1589–1593 | Article | PubMed | ISI | ChemPort |
13. Mulatero P et al. (2004) Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 89: 1045–1050 | Article | PubMed | ISI | ChemPort |
14. Mosso L et al. (2003) Primary aldosteronism and hypertensive disease. Hypertension 42: 161–165 | Article | PubMed | ISI | ChemPort |
15. Gordon RD et al. (1994) High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin Exp Pharmacol Physiol 21: 315–318 | PubMed | ISI | ChemPort |
16. Loh KC et al. (2000) Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab 85: 2854–2859 | Article | PubMed | ISI | ChemPort |
17. Fardella CE et al. (2000) Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab 85: 1863–1867 | Article | PubMed | ISI | ChemPort |
18. Lim PO et al. (2000) High prevalence of primary aldosteronism in the Tayside hypertension clinic population. J Hum Hypertens 14: 311–315 | Article | PubMed | ISI | ChemPort |
19. Schwartz GL and Turner ST (2005) Screening for primary aldosteronism in essential hypertension: diagnostic accuracy of the ratio of plasma aldosterone concentration to plasma renin activity. Clin Chem 51: 386–394 | Article | PubMed | ISI | ChemPort |
20. Hamlet SM et al. (1985) Is aldosterone/renin ratio useful to screen a hypertensive population for primary aldosteronism? Clin Exp Pharmacol Physiol 12: 249–252 | PubMed | ISI | ChemPort |
21. Calhoun DA et al. (2002) Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension 40: 892–896 | Article | PubMed | ISI | ChemPort |
22. Gallay BJ et al. (2001) Screening for primary aldosteronism without discontinuing hypertensive medications: plasma aldosterone–renin ratio. Am J Kidney Dis 37: 699–705 | PubMed | ISI | ChemPort |
23. Pratt JH et al. (1999) Levels of mineralocorticoids in whites and blacks. Hypertension 34: 315–319 | PubMed | ISI | ChemPort |
24. Rayner BL et al. (2001) Screening for primary aldosteronism—normal ranges for aldosterone and renin in three South African population groups. S Afr Med J 91: 594–599 | PubMed | ISI | ChemPort |
25. Conn JW et al. (1965) Normokalemic primary aldosteronism: a detectable cause of curable "essential" hypertension. JAMA 193: 200–206 | PubMed | ChemPort |
26. Mulatero P et al. (2002) Drug effects on aldosterone/plasma renin activity ratio in primary aldosteronism. Hypertension 40: 897–902 | Article | PubMed | ISI | ChemPort |
27. Rossi E et al. (2002) High prevalence of primary aldosteronism using postcaptopril plasma aldosterone to renin ratio as a screening test among Italian hypertensives. Am J Hypertens 15: 896–902 | Article | PubMed | ISI | ChemPort |
28. Brown NJ (2005) Aldosterone and end-organ damage. Curr Opin Nephrol Hypertens 14: 235–241 | PubMed | ISI | ChemPort |
29. Brilla CG et al. (1990) Remodeling of the rat right and left ventricles in experimental hypertension. Circ Res 67: 1355–1364 | PubMed | ISI | ChemPort |
30. Rocha R et al. (2002) Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol 283: H1802–1810 | PubMed | ISI | ChemPort |
31. Takeda Y et al. (2001) Effects of high sodium intake on cardiovascular aldosterone synthesis in stroke-prone spontaneously hypertensive rats. J Hypertens 19: 635–639 | Article | PubMed | ISI | ChemPort |
32. Kozakova M et al. (2003) Myocardial ultrasonic backscatter in hypertension: relation to aldosterone and endothelin. Hypertension 41: 230–236 | Article | PubMed | ISI | ChemPort |
33. Stowasser M et al. (2005) Evidence for abnormal left ventricular structure and function in normotensive individuals with familial hyperaldosteronism type I. J Clin Endocrinol Metab 90: 5070–5076 | Article | PubMed | ISI | ChemPort |
34. Milliez P et al. (2005) Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 45: 1243–1248 | Article | PubMed | ISI | ChemPort |
35. Pitt B et al. (2003) Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 348: 1309–1321 | Article | PubMed | ISI | ChemPort |
36. Zannad F et al. (2000) Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the Randomized Aldactone Evaluation Study (RALES). Circulation 102: 2700–2706 | PubMed | ISI | ChemPort |
37. Fallo F et al. (2006) Prevalence and characteristics of the metabolic syndrome in primary aldosteronism. J Clin Endocrinol Metab 91: 454–459 | PubMed | ISI | ChemPort |
38. Chhokar VS et al. (2005) Hyperparathyroidism and the calcium paradox of aldosteronism. Circulation 111: 871–878 | Article | PubMed | ISI | ChemPort |
39. Young WF Jr (2003) Minireview: primary aldosteronism—changing concepts in diagnosis and treatment. Endocrinology 144: 2208–2213 | Article | PubMed | ISI | ChemPort |
40. Blumenfeld JD et al. (1994) Diagnosis and treatment of primary hyperaldosteronism. Ann Intern Med 121: 877–885 | PubMed | ISI | ChemPort |
41. Mansoor GA et al. (2002) Unilateral adrenal hyperplasia causing primary aldosteronism: limitations of I-131 norcholesterol scanning. Am J Hypertens 15: 459–464 | Article | PubMed | ISI |
42. Seccia TM et al. (2005) Aldosterone-producing adrenocortical carcinoma: an unusual cause of Conn's syndrome with an ominous clinical course. Endocr Relat Cancer 12: 149–159 | Article | PubMed | ISI |
43. Mulatero P et al. (2004) Genetics of primary aldosteronism. J Hypertens 22: 663–670 | Article | PubMed | ISI | ChemPort |
44. So A et al. (2005) Familial hyperaldosteronism type II is linked to the chromosome 7p22 region but also shows predicted heterogeneity. J Hypertens 23: 1477–1484 | PubMed | ISI | ChemPort |
45. Young WF Jr (2003) Primary aldosteronism—treatment options. Growth Horm IGF Res 13 (Suppl A): S102–S108 | Article |
46. Montori VM et al. (2001) Validity of the aldosterone–renin ratio used to screen for primary aldosteronism. Mayo Clin Proc 76: 877–882 | PubMed | ISI | ChemPort |
47. Kaplan NM (2004) The current epidemic of primary aldosteronism: causes and consequences. J Hypertens 22: 863–869 | Article | PubMed | ISI | ChemPort |
48. Lamarre-Cliche M et al. (2005) Effects of circadian rhythms, posture, and medication on renin-aldosterone interrelations in essential hypertensives. Am J Hypertens 18: 56–64 | Article | PubMed | ISI | ChemPort |
49. Hirohara D et al. (2001) Performance of the basal aldosterone to renin ratio and of the renin stimulation test by furosemide and upright posture in screening for aldosterone-producing adenoma in low renin hypertensives. J Clin Endocrinol Metab 86: 4292–4298 | Article | PubMed | ISI | ChemPort |
50. Montori VM and Young WF Jr (2002) 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 31: 619–632 | Article | PubMed | ISI | ChemPort |
51. Tiu SC et al. (2005) The use of aldosterone-renin ratio as a diagnostic test for primary hyperaldosteronism and its test characteristics under different conditions of blood sampling