Curr Hypertens Rep (2014) 16:439 DOI 10.1007/s11906-014-0439-7 RESISTANT HYPERTENSION (E PIMENTA, SECTION EDITOR) Aldosterone Excess and Resistant Hypertension: Investigation and Treatment Michael Stowasser Published online: 3 May 2014 # Springer Science+Business Media New York 2014 Abstract Among patients with resistant hypertension, primary aldosteronism (PA) is worth detecting as it appears to be particularly common in this cohort. It is associated with excessive cardiovascular morbidity in relation to the degree of hypertension and reduced quality of life, both of which can be abrogated with specific surgical or medical treatment. Knowledge concerning factors (including medications) which can influence the results of screening by aldosterone/renin ratio (ARR) testing is expanding, and is important to appreciate, particularly in patients with resistant hypertension, in whom the need for multiple medications can render interpretation challenging. Advances in approaches to confirmatory testing, subtype differentiation and assay methodology are helping to improve feasibility and reliability of the diagnostic workup for PA and new treatment approaches are emerging. Major developments in understanding the genetic bases for PA hold promise towards further improvements and options in diagnosis and therapy. Keywords Aldosterone . Primary aldosteronism . Prevalence . Complications . Quality of life . Screening . Aldosterone/renin ratio . Confirmation . Subtype differentiation . Adrenal venous sampling . Treatment . Genetics . Familial This article is part of the Topical Collection on Resistant Hypertension M. Stowasser Endocrine Hypertension Research Centre, Greenslopes and Princess Alexandra Hospitals, University of Queensland School of Medicine, Ipswich Road, Woolloongabba, Queensland 4102, Australia M. Stowasser (*) Hypertension Unit, Princess Alexandra Hospital, University of Queensland School of Medicine, Ipswich Road, Woolloongabba, Queensland 4102, Australia e-mail: [email protected] Introduction Within the context of resistant hypertension, primary aldosteronism (PA) holds particular relevance as it is highly prevalent in this population (affecting possibly 15 – 20 % of patients [1, 2]), associated with excessive morbidity in relation to degree of hypertension [3], and yet can be specifically treated or even cured with marked beneficial outcomes in terms of control of hypertension, target organ function, risk of morbid events and quality of life. This report will review some of the advances that have been made over the last few years in the diagnostic workup and treatment of this important condition. Non-Blood Pressure-Dependent Adverse Effects of Aldosterone Excess: Why Detection of PA is Important Numerous published studies have demonstrated aldosterone excess to have adverse cardiovascular and renal effects which are at least partly independent of its effects on blood pressure [3-6]. Savard and co-workers [7•] recently provided further confirmation of this by comparing the prevalence of cardiovascular events in 459 patients with PA and 1,290 controls with essential hypertensives matched for sex, age and office systolic blood pressure. The prevalence of left ventricular hypertrophy was about twice as high in patients with PA, even after adjustment for hypertension duration, and PA patients had significantly higher prevalence rates for coronary artery disease, nonfatal myocardial infarction, heart failure and atrial fibrillation. Similarly, Mulatero et al. [8] reported patients with PA (n=270) to have a higher rate of cardiovascular events (and especially strokes and arrhythmias) than essential hypertensives (n=810), matched 1:3 in a case-control fashion for sex, age, blood pressure levels, duration of hypertension, body mass index, smoking habits, and comorbidity for type II diabetes mellitus. This was the case for both patients with 439, Page 2 of 11 aldosterone-producing adenoma (APA) and those with bilateral adrenal hyperplasia (BAH). Patients with PA were also more likely to develop type II diabetes during a 12-year period of follow up after diagnosis, in keeping with findings of others of a higher prevalence of diabetes and metabolic syndrome in PA patients compared with essential hypertensives [9, 10], and a role of aldosterone in disturbed glucose metabolism and insulin resistance [11, 12]. In a recent German study, mean glucose-induced, first-phase insulin secretion was reduced in a group of 22 patients with PA compared to that in 11 patients with essential hypertension, and improved in nine with APA following unilateral adrenalectomy [13]. These findings are consistent with a negative effect of aldosterone excess on pancreatic beta-cell function as being another potential explanation for higher rates of diabetes in PA. Using cardiovascular magnetic resonance imaging (MRI) to measure aortic distensibility, Mark and colleagues [14] reported that PA patients (n=14) displayed increased arterial stiffness compared with matched essential hypertensives (n= 33). Su et al. reported MRI evidence of increased myocardial fibrosis and stiffening among 25 patients with PA versus 12 age- (but not blood pressure-) matched normotensive controls [15]. Lin and co-workers found cyclical variation of integrated backscatter (a marker of left ventricular systolic function) on echocardiography to be lower, and plasma procollagen levels higher, among 20 patients with APA compared to 20 with essential hypertension, with improvements in the APA group following adrenalectomy [16]. In a separate report, these investigators described higher carotid intima-medial thicknesses on duplex ultrasound scanning, and higher arterial pulse wave velocities in the patients with APA, again improving after surgery [17]. These findings are consistent with those of previous experimental and clinical studies demonstrating that aldosterone excess can lead in a non-blood pressure-dependent way to cardiovascular remodelling via inflammation and fibrosis, and that specific treatment can abrogate these effects. In a multivariate regression analysis of 54 patients with PA followed for a mean of 6.4 years after unilateral adrenalectomy or commencement of spironolactone, Catena et al. found that the degree of reduction in left ventricular mass was independently predicted not only by change in systolic blood pressure, but also by pre-treatment plasma aldosterone levels [18], further supporting a role for aldosterone in promoting left ventricular hypertrophy that is independent of the hypertension-related hemodynamic load. Evidence is mounting that PA brings about adverse psychological effects and is associated with reduced quality of life. Some of these could be attributable to nocturia and consequent reduced sleep, frequently seen in both hypokalemic and normokalemic PA. Other symptoms may be related to hypokalemia, medications and obstructive sleep apnoea (which is common in PA and possibly a pathophysiological consequence of it [19]), and putatively direct effects of aldosterone excess, in conjunction with salt, on the central nervous Curr Hypertens Rep (2014) 16:439 system. Sonino and co-workers [20•] found a higher incidence of anxiety disorder (52.2 %) among patients with PA compared with essential hypertensives (17.4 %) and normotensive controls (4.3 %). Houlihan [21] described a patient with episodic rage which resolved after unilateral adrenalectomy for APA. Sukor et al. [22] found quality of life, measured across eight domains by SF-36 questionnaire, to be reduced in 22 Australian patients with unilateral PA when compared to general Australian population norms. Within 3 months postunilateral adrenalectomy, scores had returned to normal and remained so at 6 months. Repeating this study in 21 patients with bilateral PA treated medically with aldosterone antagonists, Ahmed et al. [23•] reported similar reductions in quality of life scores to those of patients with unilateral disease, but improvements after commencement of treatment took longer and were less complete. The above findings argue for early diagnosis and institution of specific treatment of PA. Screening for PA: Special Considerations in Resistant Hypertension As has been described in detail in previous reviews [24-26] (Table 1), a number of factors (including antihypertensive medications, posture, time of day, sodium intake, plasma potassium level, renal impairment, pregnancy and malignant hypertension) can affect the results of plasma ARR testing and need to be avoided if possible, or their effects should at least be taken into account when screening for PA. For patients with resistant hypertension, the need for multiple medications can make it difficult to obtain ARR results that are free of potential drug-induced influences. Ideally, this is achieved without losing control of hypertension by gradually replacing (if necessary in an inpatient setting) each potentially interfering agent with others (for example, verapamil slow-release±hydralazine, and prazosin or doxazosin) which have lesser effects on the ratio and then waiting several weeks (at least four after ceasing diuretics and at least two for other interfering agents) before blood collection, but this is not always possible. In cases where a potentially interfering medication cannot be withdrawn, useful information can still be obtained by taking into account its known effects when interpreting the ARR result. For example, a raised ratio in patients receiving a diuretic, angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor blocker or dihydropyridine calcium blocker (which can all cause false negatives) would make PA very likely, whereas a normal ARR in the presence of beta-blocker, clonidine or alpha-methyldopa treatment (which can cause false positives) would make the diagnosis very unlikely. Where patients are receiving drugs from both categories (for example, a beta-blocker and an ACE inhibitor), an initial ARR result can at least inform as to which to try to withdraw first Curr Hypertens Rep (2014) 16:439 Page 3 of 11, 439 Table 1 Previously established and newly reported factors affecting the aldosterone/renin ratio (ARR) in screening for primary aldosteronism (PA). Factors potentially causing false positive ARRs Factors potentially causing false negative ARRs Previously established (reviewed in [24-26]) Beta-adrenoceptor blockers Clonidine α-methyldopa Non-steroidal anti-inflammatory drugs Age > 65 years High sodium dietary intake Chronic renal impairment Newly reported (since 2011) Female gender (especially premenopausal and during luteal phase [29])* Estrogen-containing oral contraceptive agents [30]* Potassium-sparing diuretics Potassium-wasting diuretics Angiotensin converting enzyme inhibitors Angiotensin II receptor blockers Dihydropyridine calcium channel blockers Low dietary sodium intake Pregnancy Concomitant renal artery stenosis Hypokalemia Selective serotonin reuptake inhibitors [31] *False positives occur in these situations only if renin is measured as direct renin concentration and not as plasma renin activity (that is, the beta-blocker if the ARR is positive, or the ACE inhibitor if it is negative) before repeating it. In a subset of patients with resistant hypertension, ARR results will remain inconclusive because of the inability to withdraw an agent or agents that could have produced the result in question. In the case of a positive ARR in a patient on a beta-blocker (or other drug that can cause false positives) which cannot be safely ceased, confirmatory suppression testing (see next section below) should “clear the air” in terms of whether the patient does or does not have PA. The more difficult issue arises when an ARR is normal in a patient obliged to receive one or more drugs (for example, a loop diuretic or an ACE inhibitor for heart failure) which stimulate renin and thereby cause false negatives. This is because an unsuppressed renin/angiotensin II system can complicate interpretation of both confirmatory suppression testing by potentially preventing suppression of aldosterone in patients who do not have PA, and adrenal venous sampling (AVS) by stimulating aldosterone production by an otherwise suppressed gland contralateral to an APA. In those circumstances, options would include maintaining patients on suitable, effective, non-specific antihypertensive treatment, or given the particularly high prevalence of PA among patients with resistant hypertension, an empiric trial with an agent that antagonizes aldosterone action (see below under “Approaches to Treatment”). For patients in this category in whom surgery might have otherwise been a treatment option and who face a poor prognosis due to poorly controlled hypertension despite maximal medical therapy (including an antagonist of aldosterone action), adrenal CT should be considered because detection of a unilateral mass lesion, particularly if PA is likely on other clinical grounds (for example, unprovoked hypokalemia and/or very high plasma aldosterone levels), may occasionally prompt consideration for AVS, despite renin being unsuppressed, in the “hope” that it lateralizes. Furthermore, large (for example, > 2.5 cm) potentially aldosterone-secreting lesions may warrant removal based on malignant potential. Screening for PA: What’s New? Recent studies have revealed further factors that can affect the ARR (Table 1). Kerstens and co-workers reported the ARR to be higher in normotensive women than in men [27]. This may help to explain why women show a higher rate of false positive ARR results [28]. We also reported the ARR to be higher in normotensive pre-menopausal women than in agematched normotensive men, and suggested a need to consider different reference ranges according to gender [29]. When direct renin concentration (DRC), but not plasma renin activity (PRA), was used to measure renin, higher ARR values were seen in the luteal phase than during the menses or follicular phases and false positives occurred [29]. False positives also occurred using DRC (but not PRA) in women receiving an oral contraceptive agent containing ethinyl estradiol and drosperinone, but not in those receiving a subdermal implant containing etonogestrel [30]. These findings led us to propose that PRA is preferable to DRC in determination of the ARR, at least in premenopausal women, and that the menses or follicular phases are the best times to collect blood for ARR testing. We recently reported that selective serotonin reuptake inhibitor antidepressants, which have been used with ever increasing frequency in recent years, significantly reduce the ARR in normotensive subjects and, therefore, potentially increase the risk of false-negative results when screening for PA [31]. Further studies in hypertensive patients, including patients with confirmed PA, are required to confirm this possibility. Given the complexity of factors now known to influence the ARR, any development that can improve its performance as a screening test would be a welcome achievement. Pizzolo and co-workers very recently reported on the use of Nterminal pro-brain natriuretic peptide (NT-proBNP) measurement as an adjunct to ARR testing in the diagnostic evaluation of patients suspected of having PA [32]. Among 132 439, Page 4 of 11 Curr Hypertens Rep (2014) 16:439 hypertensive subjects who underwent ARR testing, of whom 81 with high ARR underwent intravenous saline infusion suppression testing (SST), NT-proBNP levels correlated positively with ARR and negatively with renin level, were higher in patients with high ARR and in those with positive SST, and were an independent predictor of positive SST. The proportion of patients with a positive SST ranged from only 23 % in females with a low NT-proBNP to 93 % in males with a high NT-proBNP, leading the authors to conclude that NT-proBNP may prove useful to identify which patients with a high ARR should receive formal confirmatory testing [32]. (eight unilateral, 11 bilateral and five undetermined subtype), 23 (96 %) tested positive by SSST compared to eight (33 %) by RSST. RSST missed one unilateral, all 11 bilateral and four with as yet undetermined subtype. RSST was positive in seven of 10 (70 %) posture-unresponsive versus one of 14 (7.1 %) posture-responsive patients. Although larger studies are required, these preliminary results suggest that SSST may be superior to RSST in terms of sensitivity for detecting PA, especially posture-responsive forms, and may represent a reliable alternative to FST. Confirmation of PA: In Search of the Optimal Approach Subtype Differentiation Because the ARR is a screening test only, and because adrenal venous sampling (AVS, required to differentiate unilateral, surgically correctable forms of PA from bilateral forms which are usually treated medically) is invasive and relatively costly, confirmatory testing is necessary to definitely confirm or exclude the diagnosis of PA in patients who screen positive. Four tests are commonly used to establish the diagnosis of PA, namely, oral sodium loading, saline infusion, fludrocortisone administration with oral sodium loading, and captopril challenge testing. Of these, fludrocortisone suppression testing (FST) has been considered the most reliable [33], but is cumbersome, difficult to perform and relatively expensive, requiring hospital admission for several days. Westerdahl and colleagues recently reported captopril challenge testing (in which the ARR is measured 120 minutes after administration of a single 25 mg dose of captopril) to have poor discriminatory power for PA in hypertensive patients with high basal ARR [34]. We previously found SST, performed in the recumbent position, to lack sensitivity for PA, missing the majority of patients (including those with APA) who tested positive by FST [35]. In keeping with our experience, Willenburg and co-workers found SST to lead to greater suppression of plasma aldosterone than FST [36]. Because aldosterone levels can be higher upright (e.g. seated) than recumbent in patients with PA, and upright levels are used during FST, we have hypothesized that seated SST (SSST) is more sensitive than recumbent SST (RSST), especially for posture-responsive PA. In a pilot study of 31 patients who underwent FST (upright plasma aldosterone levels measured at 10 a.m. basally, after 4 days of fludrocortisone 0.1 mg every 6 h, and oral salt loading) and SST (aldosterone levels measured basally at 8 a.m. and after infusion of 2 L normal saline over 4 h) both recumbent and seated in randomised order and at least 2 weeks apart, FST confirmed PA in 23 patients, excluded PA in three, and was originally “inconclusive” in five [unpublished data]. However, one with “inconclusive” FST had PA confirmed by lateralizing AVS and was reclassified “unilateral PA”. Of the 24 with confirmed PA Traditionally, PA has been divided into four main subtypes: APA, BAH, aldosterone-producing carcinoma and a rare familial form which is glucocorticoid-remediable (familial hyperaldosteronism type I or FH-I). From the practical management point of view, it is helpful to subdivide patients according to the following issues: (1) Does the patient have FH-I? If so, an excellent clinical response to glucocorticoids, given in low doses, would be expected and family screening should be undertaken to identify similarly affected relatives; (2) If FH-I has been excluded or at least is highly unlikely, is autonomous aldosterone production confined to one adrenal (consistent with APA), in which case unilateral adrenalectomy would be expected either to cure hypertension or at least result in a substantial improvement in control, or is it bilateral (consistent with BAH), in which case medical management with an agent that antagonizes aldosterone action such as spironolactone, eplerenone or amiloride would be the preferred approach; (3) Does the patient have a large adrenal mass lesion (for example, > 2.5 cm) on adrenal computed tomography (CT) scanning? If so, it deserves at least longterm follow-up and may warrant consideration of removal based on its malignant potential. The first and third of the above questions can be answered by performing genetic testing on peripheral blood for the “hybrid gene” mutation that causes FH-I [37, 38] and adrenal CT scanning, respectively. Addressing the second is more challenging. The presence of a mass lesion in one adrenal gland on CT does not confirm unilateral PA as the lesion could be non-functioning, and the aldosterone excess could be bilateral or even contralateral to it. Conversely, the lack of a mass lesion on CT does not prove bilateral PA as around 50 % of APAs (mainly those <1 cm in size) are missed on CT [39, 40]. Furthermore, unilateral PA can exist without a definable tumor (so-called unilateral adrenal hyperplasia), with two recent studies both reporting that this entity was not rare, and was associated with similar excellent long-term results following unilateral adrenalectomy [41, 42]. For these reasons, the only reliable way to differentiate unilateral from Curr Hypertens Rep (2014) 16:439 bilateral PA and to lateralize PA pre-operatively is by adrenal venous sampling (AVS). Achieving high success rates for cannulation of the adrenal veins (and especially the right, which is more difficult to locate) represents a challenge to institutions offering AVS. Recent studies have demonstrated that limiting the number of proceduralists at each institution to one or two and providing them with a higher throughput of procedures probably have the most profound effects on improving cannulation success rates [43, 44••]. Rapid, point-of-care cortisol assays have proven useful in being able to alert the proceduralist at the time of AVS, whether adrenal venous blood has been successfully obtained and, if not, whether further attempts should be made at sampling before the procedure is terminated. These have also resulted in higher success rates in centers using this technique [45-47]. We previously reported on the use of CT to localize the right adrenal vein prior to AVS [35, 48]. In a novel twist to this approach, the use of CT during angiography to determine correctness of catheter placement was recently reported by two groups to lead to catheter repositioning in a substantial proportion (approximately 10 % in each study) of patients and to be associated with the achievement of high (>90 %) rates of successful cannulation [49, 50]. Several groups have reported apparently improved success rates (based on adrenal/peripheral venous cortisol gradients) with the use of corticotrophin (ACTH) stimulation during AVS [51, 52]. Presumably, at least in some of these instances, cannulation had already been achieved but not confirmed by cortisol gradients because of a transient lack of cortisol production at the time of sampling. A concern about ACTH stimulation has been that, in a patient with APA, ACTH could lead to stimulation of the contralateral gland, causing results to suggest bilateral, rather than unilateral, disease. In the study by Monticone and co-workers [52], use of more stringent (for example, adrenal/peripheral venous cortisol gradients of > 3.0 basally and > 4.0 post-ACTH) criteria for cannulation proved important, and strongly advised, for optimizing pre- versus post-ACTH diagnostic reproducibility. Recent studies have reported on relatively high prevalence rates (>10 %) of autonomous tumorous co-secretion of cortisol in patients with APA, even in the absence of obvious clinical features of Cushing syndrome (so-called subclinical Cushing syndrome) [53, 54]. This has implications not only for peri-operative management with the need, at least some patients, to consider glucocorticoid replacement, but also for interpretation of AVS results, given that cortisol levels are required for assessment of both cannulation success and lateralization. Co-secretion of cortisol would be expected to raise cortisol levels in the adrenal vein draining the APA, while causing chronic suppression of ACTH, and thus lowering of cortisol secretion by the contralateral gland. One potential solution to this problem is the measurement of an alternative adrenal hormone to cortisol, and preferably one not influenced Page 5 of 11, 439 substantially by prevailing ACTH levels. Dekkers and coworkers [55], for example, reported on the measurement of plasma metanephrine during AVS and found it to be superior to measuring cortisol in assessing success of cannulation during AVS when performed without ACTH stimulation, with adrenal/peripheral rations sixfold higher among procedures deemed to be successful according to cortisol criteria. Baba et al. [56] reported catecholamine levels to be useful for judging not only cannulation success but also lateralization. Because AVS is relatively costly, invasive and requires considerable expertise, many attempts have been made to develop reliable alternative approaches, but with limited success. Using a clinical prediction score similar to those reported in the 1970s, Küpers et al. [57] found presence of a unilateral mass lesion on CT “typical” for APA plus a serum potassium of < 3.5 mmol/L or an estimated glomerular filtration rate of at least 100 ml/min/1.73 m2 to have 100 % specificity but only 53 % sensitivity for unilateral PA. Applying this score to the German Conn’s Registry, Riester and co-workers [58] were not able to reproduce this high specificity, except in individuals under 40 years of age. Candy et al. [59] also found a lower specificity of 88 % for the clinical prediction score among a UK cohort of patients with PA, and were unable to show superiority over an imaging-based strategy. Other promising new approaches for differentiating APA from BAH, which require validation in different centers and with larger numbers, have included the use of semiquantification of 131I6β-iodomethyl-norcholesterol (NP-59) single photon emission computed tomography (SPECT)/CT [60] and 11Cmetomidate positron emission tomography (PET)-CT [61]. A major barrier to the validation of various approaches to distinguishing unilateral from bilateral PA has been the lack of a robust “gold standard” for diagnosing APA. Many studies have relied on suboptimal approaches, including the demonstration of an adenoma in surgically removed adrenals (without firm evidence as to whether it was actually producing aldosterone), the blood pressure response to surgery (which may be incomplete if the patient is studied too soon after adrenalectomy or has other causes of residual hypertension) and the response to surgery of plasma aldosterone plus or minus renin levels (which is better, but still imperfect as cutoff criteria are arbitrary to some extent, and the ARR is associated with false positives and negatives). Our own approach is to repeat the FST post-operatively [62], but, as stated above, this is time consuming and cumbersome to perform. Recent studies have reported on the use of immunohistochemical staining of removed adrenals in an attempt to confirm APA removal [63-65]. Using isoform-specific monoclonal antibodies against the 3β-hydroxysteroid dehydrogenase/ isomerase family, Doi and co-workers reported hyperplasia of zona glomerulosa seen in BAH to be accompanied by a robust expression of the HSD3B1 isoform [63]. In contrast, tumor cells in APA were not immunopositive to HSD3B1 but 439, Page 6 of 11 showed expression of HSD3B2. Volpe and colleagues found APAs to show strong immunoreactivity for aldosterone synthase [65]. In adrenals from seven patients, they found either “adenomas” (presumably defined as adrenocortical tumors of at least 1 cm in diameter) that were not CYP11B2 positive (n= 4) or no “adenoma” at all (n=3), but smaller nodules with strong CYB11B2 immunoreactivity, indicating aldosteroneproducing nodular hyperplasia. Nanba et al., in a study of 32 patients with PA who underwent unilateral adrenalectomy, found 22 to show positive CYP11B2 immunostaining in their tumors (designated APAs), and eight with either CYP11B2negative adenomas (n=4) or without tumors on CT to show aldosterone-producing cell clusters (APCCs) with CYP11B2 immunostaining in the zona glomerulosa [64]. In APAs, CYP11B2 score adjusted for tumor volume was positively correlated with plasma aldosterone and negatively with serum potassium. APAs with either similar or greater amounts of CYP11B1 (11β-hydroxylase, which catalyzes the last step of cortisol biosynthesis) to CYP11B2 staining showed significantly higher serum cortisol after 1 mg dexamethasone and larger tumor size than the CYP11B2-dominant APA group. Importance of Subtype Differentiation It has been argued that, given the effort and expense involved, diagnostic workup for PA (and especially subtype differentiation) can be avoided by simply using spironolactone or eplerenone as first-line agents in every patient suspected of having the condition [66, 67] or even in every new hypertensive [68, 69]. However, this approach would deny patients with unilateral PA (who constitute approximately 30 % of PA patients [70]) the chance of a surgical cure or at least a marked reduction in medication requirements. Perhaps surprisingly, the mean number of medications taken by PA patients to control hypertension after commencing an aldosterone antagonist (if the antagonist is counted as one) does not fall [39]. By contrast, 40 – 80 % of patients who had surgery are cured of hypertension and able to come off all antihypertensive medications, and the great majority of the remainder are on fewer antihypertensives than pre-operatively [22, 39, 62, 71]. For both cardiovascular outcomes [72, 73, 74••] and quality of life [22, 23•], beneficial effects of surgery in unilateral PA have been reported to be superior (more marked and/or more rapid) to those of medical therapy in bilateral PA. A nationwide epidemiological study conducted in Japan which analysed data from 1,706 patients with PA found that, among those with APA, surgical, but not medical, treatment was significantly associated with amelioration of hypertension [75•]. By contrast, among patients with hyperplastic forms of PA (mostly BAH), there was no relationship between surgical or medical treatment and the prognosis of hypertension. In an observational study reported by Reinke and Curr Hypertens Rep (2014) 16:439 colleagues on 300 patients with PA, adrenalectomy (presumably mostly for unilateral PA) was associated with reduced allcause mortality when compared with medical treatment [76]. Most of our patients who undergo unilateral adrenalectomy for unilateral PA report a marked improvement in general wellbeing that is much less apparent in patients with bilateral disease treated medically. Even in doses as low as 12.5 to 50 mg daily, treatment with spironolactone can be accompanied by side effects such as gynaecomastia, loss of libido and menstrual irregularities [39], and eplerenone (a more selective mineralocorticoid receptor antagonist which minimises sex steroid-related side effects) is not available as a costsubsidized agent for treatment of hypertension in many countries, making the cost prohibitive for most patients with PA. Towards High Quality Assay Development Because each phase of the diagnostic workup of PA (screening, confirmation and subtype differentiation) is dependent on accurate measurement of plasma aldosterone, and because the ARR is predominantly renin-dependent, it is critical that the methods used to assay aldosterone and renin in clinical samples are of high quality. Recent years have seen laboratories moving towards using autom ated platforms and immunometric methodology, primarily on the basis of faster throughput and lower cost, and potentially at the expense of lower reliability. In an attempt to address such concerns, we recently reported on the development of a high-throughput method of measuring plasma aldosterone using high performance liquid chromatography and tandem mass spectrometry (LC-MS/MS) which proved to be highly accurate and reproducible [77]. Since then, several other investigators have established similar assays for aldosterone [78, 79], and at least two groups have developed assays which use LC-MS/MS to measure angiotensin I and thereby determine PRA [80, 81]. As discussed above, PRA is less likely than DRC to result in falsely elevated ARR values in pre-menopausal women [29, 30]. Incorporation of LC-MS/MS technology into routine clinical laboratory practice for measuring aldosterone and renin promises to be a major step forward for optimal detection and diagnosis of PA and its subtypes. Approaches to Treatment The mainstays of treatment for PA continue to be unilateral adrenalectomy for most patients with unilateral forms (in our experience leading to cure of hypertension in 60 – 80 % and improvement in almost all of the remainder [22, 39, 62]), and medications that antagonise aldosterone action (for example, spironolactone 12.5 – 50 mg daily, eplerenone 25 – 100 mg daily or amiloride 2.5 – 20 mg daily) for most with bilateral Curr Hypertens Rep (2014) 16:439 PA. Both treatment approaches can result in marked blood pressure lowering in patients with hypertension, including those with resistant forms. Recent surgical developments have included reports of single incision laparoscopic adrenalectomy [82, 83], which offers superior cosmetic results to multiple incision approaches but requires further experience to establish its value from a risk versus benefit perspective. On the medical front, a long-awaited paper reporting results from a randomized, double blinded trial comparing the efficacy, safety and tolerability of eplerenone to that of spironolactone (given in relatively large daily doses of 100 – 300 mg and 75 – 225 mg respectively) in patients with PA declared spironolactone to be superior in terms of blood pressure lowering, but to be associated, as expected, with higher rates of male gynecomastia (21 % versus 5 % for eplerenone) and female mastodynia (21 % versus 0 %) [84]. Aldosterone synthase inhibitors remain a promising new treatment approach, despite a recent study showing that in patients with PA, the effects on blood pressure and plasma potassium and renin concentrations of eplerenone treatment (50 – 100 mg twice daily) were more marked than those of 4 weeks of treatment with the aldosterone synthase inhibitor LCI699 (0.5 – 1 mg twice daily) [85]. As expected, eplerenone raised while LC1699 lowered plasma aldosterone concentrations. An ongoing concern for these new drugs is the potential for inhibiting cortisol production in addition to that of aldosterone. Non-steroidal dihydropyridine-based mineralocorticoid receptor antagonists [86, 87] are a new drug class which have displayed similar in vitro potency to spironolactone, and without apparent effects on androgen and progesterone receptors. These drugs therefore hold the promise of blood pressure lowering effects in PA that are at least equivalent to those of spironolactone but without the sex steroid-related side-effects, and superior to those of eplerenone. BAY 94-8862, the firstin-class of this new generation of mineralocorticoid receptor antagonists, is currently in development for treatment of heart failure [86], with early results showing considerable promise [88], and studies in PA are eagerly awaited. Recent studies in humans have demonstrated that, similarly to animals, endogenous aldosterone and dietary salt intake interact to accelerate target-organ deterioration. Pimenta and colleagues demonstrated both the left ventricular mass [89] and the degree of proteinuria [90] in patients with PA to be dependent on 24-h sodium excretion rate (as a marker of dietary salt intake). Increased dietary sodium and aldosterone were also shown by these workers to be related to severity of obstructive sleep apnea in patients with resistant hypertension [91]. It therefore, stands to reason that incorporation of dietary salt restriction in the management of patients with PA may help to limit and even reverse target organ damage and morbidity. Page 7 of 11, 439 The New Genetics Although perhaps less obviously associated with investigation and treatment in the immediate sense, no update on PA would be complete without mention of the major recent advances that have been made in understanding the genetic basis of this disorder. Perhaps the most exciting of these is the finding that not only are germline mutations in the KCNJ5 potassium channel gene associated with familial primary aldosteronism [92••, 93-95], but somatic mutations in the same channel have been identified within APAs with a frequency of approximately 40 % in Caucasian patients [92••, 96-100] and even higher in Japanese patients [101]. Somatic mutations within APAs have also been described in CACNA1D (encoding a voltage-gated calcium channel), ATP1A1 (encodes the αsubunit of Na+/K+ ATPase) and ATP2B3 (encodes a Ca2+ ATPase calcium channel) [102•, 103•, 104]. We resequenced the flanking and coding region of KCNJ5 in peripheral blood DNA from 251 Caucasian subjects with PA to look for rare variants that might be important for the pathophysiology of sporadic forms and identified three heterozygous missense mutations (R52H, E246K and G247R) in the cohort and found that 12 (5 % of the cohort) were carriers for the rare non-synonymous single nucleotide polymorphism rs7102584 causing E282Q substitution of KCNJ5 [105]. Unlike other previously described mutations associated with PA, these three mutations and rare polymorphism were all remote from the potassium channel selectivity filter. By expressing the channels in Xenopus oocytes and human adrenal H295R cells, we showed that the R52H, E246K and E282Q (but not G247) substitutions were functional, affecting the inward rectification, the ability of the KCNJ5 channels to conduct Na + currents and angiotensin II-induced aldosterone release from the H295R cell line [105]. Together these data suggest that germline variation in the KCNJ5 gene has a role to play in the common sporadic form as well as the much rarer syndromic forms of PA. Conclusions The difficulty of obtaining hypertension control, the high prevalence of PA, and the fact that aldosterone excess adds to the burden of morbidity in ways that go above and beyond hypertension itself, all argue for the need to screen for PA in patients with resistant hypertension. In fact, given the confounding effects of medications on the ARR, an argument can be made for screening before hypertension reaches the stage of needing multiple (or even before commencing) drug treatment. Advances in approaches to confirmatory testing, subtype differentiation, assay technology and treatment are helping to allow treating physicians to diagnose and provide optimal management to patients with this condition. New 439, Page 8 of 11 knowledge concerning the genetic basis for PA may also ultimately lead to new ways of detecting and treating these patients among the resistant hypertension population. Curr Hypertens Rep (2014) 16:439 12. 13. Compliance with Ethics Guidelines Conflict of Interest Michael Stowasser declares that he has no conflict of interest. 14. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. 15. 16. References 17. Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 18. 19. 1. 2. 3. 4. 5. 6. 7.• 8. 9. 10. 11. Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension. 2002;40:892–6. Gallay BJ, Ahmad S, Xu L, Toivola B, Davidson RC. Screening for primary aldosteronism without discontinuing hypertensive medications: plasma aldosterone-renin ratio. Am J Kidney Dis. 2001;37:699–705. Catena C, Colussi G, Nadalini E, Chiuch A, Baroselli S, Lapenna R, et al. Cardiovascular outcomes in patients with primary aldosteronism after treatment. Arch Intern Med. 2008;168:80–5. Rossi GP, Bernini G, Desideri G, Fabris B, Ferri C, Giacchetti G, et al. Renal damage in primary aldosteronism: results of the PAPY Study. Hypertension. 2006;48:232–8. Rossi GP, Cesari M, Pessina AC. Left ventricular changes in primary aldosteronism. Am J Hypertens. 2003;16:96–8. Stowasser M. New perspectives on the role of aldosterone excess in cardiovascular disease. Clin Exp Pharmacol Physiol. 2001;28: 783–91. Savard S, Amar L, Plouin PF, Steichen O. Cardiovascular complications associated with primary aldosteronism: a controlled crosssectional study. Hypertension. 2013;62:331–6. This large retrospective study reported that, compared with essential hypertensives (n= 459) matched for age, sex and office systolic blood pressure, patients with PA (n=1290) were more likely to have left ventricular hypertrophy or coronary artery disease, and to have suffered a nonfatal myocardial infarct, heart failure or atrial fibrillation. Mulatero P, Monticone S, Bertello C, Viola A, Tizzani D, Iannaccone A, et al. Long-term cardio- and cerebrovascular events in patients with primary aldosteronism. J Clin Endocrinol Metab. 2013;98:4826–33. Fallo F, Veglio F, Bertello C, Sonino N, Della Mea P, Ermani M, et al. Prevalence and characteristics of the metabolic syndrome in primary aldosteronism. J Clin Endocrinol Metab. 2006;91:454–9. Reincke M, Meisinger C, Holle R, Quinkler M, Hahner S, Beuschlein F, et al. Is primary aldosteronism associated with diabetes mellitus? Results of the German Conn's Registry. Horm Metab Res. 2010;42:435–9. Fallo F, Della Mea P, Sonino N, Bertello C, Ermani M, Vettor R, et al. Adiponectin and insulin sensitivity in primary aldosteronism. Am J Hypertens. 2007;20:855–61. 20.• 21. 22. 23.• 24. 25. 26. 27. 28. Williams TA, Monticone S, Urbanet R, Bertello C, Giraudo G, Vettor R, et al. Genes implicated in insulin resistance are downregulated in primary aldosteronism patients. Mol Cell Endocrinol. 2012;355:162–8. Fischer E, Adolf C, Pallauf A, Then C, Bidlingmaier M, Beuschlein F, et al. Aldosterone excess impairs first phase insulin secretion in primary aldosteronism. J Clin Endocrinol Metab. 2013;98:2513–20. Mark PB, Boyle S, Zimmerli LU, McQuarrie EP, Delles C, Freel EM. Alterations in vascular function in primary aldosteronism: a cardiovascular magnetic resonance imaging study. J Hum Hypertens. 2014;28:92–7. Su MY, Wu VC, Yu HY, Lin YH, Kuo CC, Liu KL, et al. Contrastenhanced MRI index of diffuse myocardial fibrosis is increased in primary aldosteronism. J Magn Reson Imaging. 2012;35:1349–55. Lin YH, Lee HH, Liu KL, Lee JK, Shih SR, Chueh SC, et al. Reversal of myocardial fibrosis in patients with unilateral hyperaldosteronism receiving adrenalectomy. Surgery. 2011. Lin YH, Lin LY, Chen A, Wu XM, Lee JK, Su TC, et al. Adrenalectomy improves increased carotid intima-media thickness and arterial stiffness in patients with aldosterone producing adenoma. Atherosclerosis. 2012;221:154–9. Catena C, Colussi GL, Marzano L, Sechi LA. Predictive factors of left ventricular mass changes after treatment of primary aldosteronism. Horm Metab Res. 2012;44:188–93. Pimenta E, Calhoun DA, Oparil S. Sleep apnea, aldosterone, and resistant hypertension. Prog Cardiovasc Dis. 2009;51:371–80. Sonino N, Tomba E, Genesia ML, Bertello C, Mulatero P, Veglio F, et al. Psychological assessment of primary aldosteronism: a controlled study. J Clin Endocrinol Metab. 2011;96:E878–83. This carefully performed case-control study found anxiety and stress to be more common among patients with PA(n=23) than those with essential hypertension (n=23). Houlihan DJ. Episodic rage associated with primary aldosteronism resolved with adrenalectomy. Psychother Psychosom. 2011;80:306–7. Sukor N, Kogovsek C, Gordon RD, Robson D, Stowasser M. Improved quality of life, blood pressure, and biochemical status following laparoscopic adrenalectomy for unilateral primary aldosteronism. J Clin Endocrinol Metab. 2010;95:1360–4. Ahmed AH, Gordon RD, Sukor N, Pimenta E, Stowasser M. Quality of life in patients with bilateral primary aldosteronism before and during treatment with spironolactone and/or amiloride, including a comparison with our previously published results in those with unilateral disease treated surgically. J Clin Endocrinol Metab. 2011;96:2904–11. Sthis study found quality of life scores among 21 patients with bilateral PA to be subnormal at baseline, and to have improved after 6 months of specific medical therapy, but more slowly and to a lesser degree than surgical treatment had previously been shown to improve quality of life scores in 22 patients with unilateral PA. Gordon RD. Primary aldosteronism. J Endocrinol Invest. 1995;18: 495–511. Stowasser M, Gordon RD. The aldosterone-renin ratio for screening for primary aldosteronism. Endocrinologist. 2004;14:267–76. Stowasser M, Taylor PJ, Pimenta E, Ahmed AH, Gordon RD. Laboratory investigation of primary aldosteronism. Clin Biochem Rev. 2010;31:39–56. Kerstens MN, Muller KAC, Volmer M, Koerts J, Sluiter WJ, Dullaart RP. Reference values for aldosterone-renin ratios in normotensive individuals and effect of changes in dietary sodium consumption. Clin Chem. 2011;57:1607–11. Pizzolo F, Raffaelli R, Memmo A, Chiecchi L, Pavan C, Guarini P, et al. Effects of female sex hormones and contraceptive pill on the diagnostic work-up for primary aldosteronism. J Clin Endocrinol Metab. 2010;28:135–42. Curr Hypertens Rep (2014) 16:439 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44.•• Ahmed AH, Gordon RD, Taylor PJ, Ward G, Pimenta E, Stowasser M. Are women more at risk of false-positive primary aldosteronism screening and unnecessary suppression testing than men? J Clin Endocrinol Metab. 2011;96:E340–6. FThis study reported (1) ARR levels to be higher in 19 normal premenopausal women than in 21 normal men, suggesting the need for new reference ranges that take gender into account; and (2) the occurrence of false-positive ARRs in two of the women during the luteal phase only when DRC (and not PRA) was used, suggesting that PRA is preferable to DRC in determination of ARR. Ahmed AH, Gordon RD, Taylor PJ, Ward G, Pimenta E, Stowasser M. Effect of contraceptives on aldosterone/renin ratio may vary according to the components of contraceptive, renin assay method, and possibly route of administration. J Clin Endocrinol Metab. 2011;96:1797–804. Ahmed AH, Calvird M, Gordon RD, Taylor PJ, Ward G, Pimenta E, et al. Effects of two selective serotonin reuptake inhibitor antidepressants, sertraline and escitalopram, on aldosterone/renin ratio in normotensive depressed male patients. J Clin Endocrinol Metab. 2011;96:1039–45. Pizzolo F, Zorzi F, Chiecchi L, Consoli L, Aprili I, Guarini P, et al. NT-proBNP, a useful tool in hypertensive patients undergoing a diagnostic evaluation for primary aldosteronism. Endocrine. 2014;45:479–86. Stowasser M, Gordon RD. Primary aldosteronism. Best Pract Res Clin Endocrinol Metab. 2003;17:591–605. Westerdahl C, Bergenfelz A, Isaksson A, Valdemarsson S. Captopril suppression: Limitations for confirmation of primary aldosteronism. J Renin Angiotensin Aldosterone Syst. 2011. Stowasser M, Gordon RD, Rutherford JC, Nikwan NZ, Daunt N, Slater GJ. Diagnosis and management of primary aldosteronism. J Renin-Angiotensin-Aldosterone Syst. 2001;2:156–69. Willenberg HS, Vonend O, Schott M, Gao X, Blondin D, Saleh A, et al. Comparison of the saline infusion test and the fludrocortisone suppression test for the diagnosis of primary aldosteronism. Horm Metab Res. 2012;44:527–32. Jonsson JR, Klemm SA, Tunny TJ, Stowasser M, Gordon RD. A new genetic test for familial hyperaldosteronism type I aids in the detection of curable hypertension. Biochem Biophys Res Commun. 1995;207:565–71. Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, et al. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 1992;355:262–5. Stowasser M, Gordon RD, Gunasekera TG, Cowley DC, Ward G, Archibald C, et al. High rate of detection of primary aldosteronism, including surgically treatable forms, after 'non-selective' screening of hypertensive patients. J Hypertens. 2003;21:2149–57. Young WF, Stanson AW, Thompson GB, Grant CS, Farley DR, van Heerden JA. Role for adrenal venous sampling in primary aldosteronism. Surgery. 2004;136:1227–35. Weisbrod AB, Webb RC, Mathur A, Barak S, Abraham SB, Nilubol N, et al. Adrenal histologic findings show no difference in clinical presentation and outcome in primary hyperaldosteronism. Ann Surg Oncol. 2013;20:753–8. Iacobone M, Citton M, Viel G, Boetto R, Bonadio I, Tropea S, et al. Unilateral adrenal hyperplasia: a novel cause of surgically correctable primary hyperaldosteronism. Surgery. 2012;152: 1248–55. Harvey A, Pasieka JL, Kline G, So B. Modification of the protocol for selective adrenal venous sampling results in both a significant increase in the accuracy and necessity of the procedure in the management of patients with primary hyperaldosteronism. Surgery. 2012;152:643–9. discussion 9-51. Vonend O, Ockenfels N, Gao X, Allolio B, Lang K, Mai K, et al. Adrenal venous sampling: evaluation of the German Conn's Page 9 of 11, 439 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. registry. Hypertension. 2011;57:990–5. This study demonstraterd the importance of high throughput in enhancing cannulation success rate and reported markedly improved success rates among German centers performing AVS after the introduction of a variety of reforms including the creation of standard AVS operating procedures, restricting the procedure to 1-2 proceduralists at each center, use of CTscanning to locate the adrenal veins prior to AVS and point-of-care cortisol testing. Betz MJ, Degenhart C, Fischer E, Pallauf A, Brand V, Linsenmaier U, et al. Adrenal vein sampling using rapid cortisol assays in primary aldosteronism is useful in centers with low success rates. Eur J Endocrinol. 2011;165:301–6. Rossi E, Regolisti G, Perazzoli F, Negro A, Grasselli C, Santi R, et al. Intraprocedural cortisol measurement increases adrenal vein sampling success rate in primary aldosteronism. Am J Hypertens. 2011;24:1280–5. Viste K, Grytaas MA, Jorstad MD, Jossang DE, Hoyden EN, Fotland SS, et al. Efficacy of adrenal venous sampling is increased by point of care cortisol analysis. Endocr Connect. 2013;2:236– 42. Daunt N. Adrenal vein sampling: how to make it quick, easy, and successful. Radiographics. 2005;25 Suppl 1:S143–58. Onozawa S, Murata S, Tajima H, Yamaguchi H, Mine T, Ishizaki A, et al. Evaluation of right adrenal vein cannulation by computed tomography angiography in 140 consecutive patients undergoing adrenal venous sampling. Eur J Endocrinol. 2014;170:601–8. Park SI, Rhee Y, Lim JS, Park S, Kang SW, Lee MS, et al. Right adrenal venography findings correlated with C-arm CT for selection during C-arm CT-assisted adrenal vein sampling in primary aldosteronism. Cardiovasc Intervent Radiol. 2013. Kline GA, Pasieka JL, Harvey A, So B, Dias VC. A marked proportional rise in IVC aldosterone following cosyntropin administration during AVS is a signal to the presence of adrenal hyperplasia in primary aldosteronism. J Hum Hyperten. 2013. Monticone S, Satoh F, Giacchetti G, Viola A, Morimoto R, Kudo M, et al. Effect of adrenocorticotropic hormone stimulation during adrenal vein sampling in primary aldosteronism. Hypertension. 2012;59:840–6. Fujimoto K, Honjo S, Tatsuoka H, Hamamoto Y, Kawasaki Y, Matsuoka A, et al. Primary aldosteronism associated with subclinical Cushing syndrome. J Endocrinol Invest. 2013;36:564–7. Lau JH, Sze WC, Reznek RH, Matson M, Sahdev A, Carpenter R, et al. A prospective evaluation of postural stimulation testing, computed tomography and adrenal vein sampling in the differential diagnosis of primary aldosteronism. Clin Endocrinol (Oxf). 2012;76:182–8. Dekkers T, Deinum J, Schultzekool LJ, Blondin D, Vonend O, Hermus AR, et al. Plasma metanephrine for assessing the selectivity of adrenal venous sampling. Hypertension. 2013;62:1152–7. Baba Y, Hayashi S, Nakajo M. Are catecholamine-derived indexes in adrenal venous sampling useful for judging selectivity and laterality in patients with primary aldosteronism? Endocrine. 2013;43:611–7. Kupers EM, Amar L, Raynaud A, Plouin PF, Steichen O. A clinical prediction score to diagnose unilateral primary aldosteronism. J Clin Endocrinol Metab. 2012;97:3530–7. Riester A, Fischer E, Degenhart C, Reiser MF, Bidlingmaier M, Beuschlein F, et al. Age below 40 or a recently proposed clinical prediction score cannot bypass adrenal venous sampling in primary aldosteronism. J Clin Endocrinol Metab. 2014:jc20133789. Candy SWC, Soh LM, Lau JH, Reznek R, Sahdev A, Matson M, et al. Diagnosing unilateral primary aldosteronism - comparison of a clinical prediction score, computed tomography and adrenal venous sampling. Clin Endocrinol (Oxf). 2013. Lu CC, Wu VC, Wu KD, Liu KL, Lin WC, Cheng MF, et al. Prognostic value of semiquantification NP-59 SPECT/CT in 439, Page 10 of 11 primary aldosteronism patients after adrenalectomy. Eur J Nucl Med Mol Imaging. 2014. 61. Burton TJ, Mackenzie IS, Balan K, Koo B, Bird N, Soloviev DV, et al. Evaluation of the sensitivity and specificity of (11)Cmetomidate positron emission tomography (PET)-CT for lateralizing aldosterone secretion by Conn's adenomas. J Clin Endocrinol Metab. 2012;97:100–9. 62. Rutherford JC, Taylor WL, Stowasser M, Gordon RD. Success of surgery for primary aldosteronism judged by residual autonomous aldosterone production. World J Surg. 1998;22:1243–5. 63. Doi M, Satoh F, Maekawa T, Nakamura Y, Fustin JM, Tainaka M, et al. Isoform-specific monoclonal antibodies against 3betahydroxysteroid dehydrogenase/isomerase family provide markers for subclassification of human primary aldosteronism. J Clin Endocrinol Metab. 2014;99:E257–62. 64. Nanba K, Tsuiki M, Sawai K, Mukai K, Nishimoto K, Usui T, et al. Histopathological diagnosis of primary aldosteronism using CYP11B2 immunohistochemistry. J Clin Endocrinol Metab. 2013;98:1567–74. 65. Volpe C, Hoog A, Ogishima T, Mukai K, Lu M, Thoren M, et al. Immunohistochemistry improves histopathologic diagnosis in primary aldosteronism. J Clin Pathol. 2013;66:351–4. 66. Kaplan NM. The current epidemic of primary aldosteronism: causes and consequences. J Hypertens. 2004;22:863–9. 67. Kaplan NM. Primary aldosteronism: evidence against a second epidemic. J Hypertens. 2012;30:1899–902. 68. Funder JW. Primary aldosteronism: are we missing the wood for the trees? Horm Metab Res. 2012;44:251–3. 69. Funder JW. Ultimately we are in furious agreement. J Hypertens. 2012;30:1903–5. 70. Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab. 2004;89:1045–50. 71. Celen O, O'Brien MJ, Melby JC, Beazley RM. Factors influencing outcome of surgery for primary aldosteronism. Arch Surg. 1996;131:646–50. 72. Catena C, Colussi G, Lapenna R, Nadalini E, Chiuch A, Gianfagna P, et al. Long-term cardiac effects of adrenalectomy or mineralocorticoid antagonists in patients with primary aldosteronism. Hypertension. 2007;50:911–8. 73. Strauch B, Petrak O, Zelinka T, Wichterle D, Holaj R, Kasalicky M, et al. Adrenalectomy improves arterial stiffness in primary aldosteronism. Am J Hypertens. 2008;21:1086–92. 74.•• Bernini G, Bacca A, Carli V, Carrara D, Materazzi G, Berti P, et al. Cardiovascular changes in patients with primary aldosteronism after surgical or medical treatment. J Endocrinol Invest. 2012;35:274–80. In this study involving 60 patients with PA (19 with APA and 41 with BAH), surgery in APA was more effective in reducing blood pressure and in reducing left ventricular massthan the use of specific medication aimed at blocking aldsoterone action in BAH, thus supporting the need to clinically differentiate these two PA subtypes. 75.• Miyake Y, Tanaka K, Nishikawa T, Naruse M, Takayanagi R, Sasano H, et al. Prognosis of primary aldosteronism in Japan: results from a nationwide epidemiological study. Endocr J. 2014;61:35–40. Analysis of data from 1706 patients with PA revealed that, (1) among those with APA, surgical, but not medical, treatment was significantly associated with amelioration of hypertension whereas (2) among patients with hyperplastic forms of PA (mostly BAH), there was no relationship between either surgical or medical treatment and the prognosis of hypertension. These findings again support subtype testing in order to identify those individuals with unilateral PA who will benefit from surgery. 76. Reincke M, Fischer E, Gerum S, Merkle K, Schulz S, Pallauf A, et al. Observational study mortality in treated primary aldosteronism: the German Conn's registry. Hypertension. 2012;60:618–24. Curr Hypertens Rep (2014) 16:439 77. Taylor PJ, Cooper DP, Gordon RD, Stowasser M. Measurement of aldosterone in human plasma by semiautomated HPLC-tandem mass spectrometry. Clin Chem. 2009;55:1155–62. 78. Hinchliffe E, Carter S, Owen LJ, Keevil BG. Quantitation of aldosterone in human plasma by ultra high performance liquid chromatography tandem mass spectrometry. J Chromatogr B. 2013;913–914:19–23. 79. Van DGJG, Dubland J, Liu HF, Wang A, Joseph C, Holmes DT. Determination of serum aldosterone by liquid chromatography and tandem mass spectrometry: a liquid-liquid extraction method for the ABSCIEX API-5000 mass spectrometry system. J Clin Pathol. 2012;65:457–62. 80. Camenzind AG, van der Gugten JG, Popp R, Holmes DT, Borchers CH. Development and evaluation of an immunoMALDI (iMALDI) assay for angiotensin I and the diagnosis of secondary hypertension. Clin Proteomics. 2013;10:20. 81. Carter S, Owen LJ, Kerstens MN, Dullaart RP, Keevil BG. A liquid chromatography tandem mass spectrometry assay for plasma renin activity using online solid-phase extraction. Ann Clin Biochem. 2012;49:570–9. The paper reported a mass spectrometric method for measuing PRA which has the potential to greatly increase reliability and reproducibility when screening for PA by ARR testing. 82. Shimabuku M, Sasaki A, Higa M, Kakazu M, Asato M, Shiroma H. Single-incision laparoscopic adrenalectomy for primary aldosteronism: report of a case. Surg Today. 2011;41:1306–9. 83. Colon MJ, Lemasters P, Newell P, Divino C, Weber KJ, Chin EH. Laparoscopic single site adrenalectomy using a conventional laparoscope and instrumentation. J Soc Laparoendosc Surg. 2011;15: 236–8. 84. Parthasarathy HK, Menard J, White WB, Young Jr WF, Williams GH, Williams B, et al. A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism. J Hypertens. 2011;29:980–90. 85. Amar L, Azizi M, Menard J, Peyrard S, Plouin PF. Sequential comparison of aldosterone synthase inhibition and mineralocorticoid blockade in patients with primary aldosteronism. J Hypertens. 2013;31:624–9. discussion 9. 86. Barfacker L, Kuhl A, Hillisch A, Grosser R, Figueroa-Perez S, Heckroth H, et al. Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases. ChemMedChem. 2012;7:1385–403. 87. Fagart J, Hillisch A, Huyet J, Barfacker L, Fay M, Pleiss U, et al. A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule. J Biol Chem. 2010;285: 29932–40. 88. Pitt B, Kober L, Ponikowski P, Gheorghiade M, Filippatos G, Krum H, et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J. 2013;34: 2453–63. 89. Pimenta E, Gordon RD, Ahmed AH, Cowley D, Leano R, Marwick TH, et al. Cardiac dimensions are largely determined by dietary salt in patients with primary aldosteronism: results of a case-control study. J Clin Endocrinol Metab. 2011;96:2813–20. 90. Pimenta E, Gordon RD, Ahmed AH, Cowley D, Robson D, Kogovsek C, et al. Unilateral adrenalectomy improves urinary protein excretion but does not abolish its relationship to sodium excretion in patients with aldosterone-producing adenoma. J Hum Hypertens. 2011;25:592–9. 91. Pimenta E, Stowasser M, Gordon RD, Harding SM, Batlouni M, Zhang B, et al. Increased dietary sodium is related to severity of obstructive sleep apnea in patients with resistant hypertension and hyperaldosteronism. Chest. 2013;143:978–83. Curr Hypertens Rep (2014) 16:439 92.•• Choi M, Scholl UI, Yue P, Bjorklund P, Zhao B, Nelson-Williams C, et al. K+channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011;331:768– 72. This landmark paper reported a germline mutation in KCNJ5, a potassium channel gene, in a family with florid PA, and somatic KCNJ5 mutations in 8 (36%) of 22 APAs. When expressed in vitro, the mutations led to increased sodium conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium entry, the signal for aldosterone production and cell proliferation. 93. Charmandari E, Sertedaki A, Kino T, Merakou C, Hoffman DA, Hatch MM, et al. A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension. J Clin Endocrinol Metab. 2012;97: E1532–9. 94. Monticone S, Hattangady NG, Penton D, Isales CM, Edwards MA, Williams TA, et al. A Novel Y152C KCNJ5 mutation responsible for familial hyperaldosteronism type III. J Clin Endocrinol Metab. 2013;98:E1861–5. 95. Mulatero P, Tauber P, Zennaro MC, Monticone S, Lang K, Beuschlein F, et al. KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism. Hypertension. 2012;59:235–40. 96. Azizan EA, Murthy M, Stowasser M, Gordon R, Kowalski B, Xu S, et al. Somatic mutations affecting the selectivity filter of KCNJ5 are frequent in 2 large unselected collections of adrenal aldosteronomas. Hypertension. 2012;59:587–91. 97. Williams TA, Monticone S, Schack VR, Stindl J, Burrello J, Buffolo F, et al. Somatic ATP1A1, ATP2B3, and KCNJ5 Mutations in Aldosterone-Producing Adenomas. Hypertension. 2014;63:188–95. 98. Akerstrom T, Crona J, Delgado VA, Starker LF, Cupisti K, Willenberg HS, et al. Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter. PLoS ONE. 2012;7:e41926. Page 11 of 11, 439 99. 100. 101. 102.• 103.• 104. 105. Scholl UI, Nelson-Williams C, Yue P, Grekin R, Wyatt RJ, Dillon MJ, et al. Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. PNAS. 2012;109:2533–8. Boulkroun S, Beuschlein F, Rossi GP, Golib-Dzib JF, Fischer E, Amar L, et al. Prevalence, clinical, and molecular correlates of KCNJ5 mutations in primary aldosteronism. Hypertension. 2012;59:592–8. Taguchi R, Yamada M, Nakajima Y, Satoh T, Hashimoto K, Shibusawa N, et al. Expression and mutations of KCNJ5 mRNA in Japanese patients with aldosterone-producing adenomas. J Clin Endocrinol Metab. 2012;97:1311–9. Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, Lichtenauer UD, et al. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet. 2013;45:440-4, 4e1-2. Subsequent to reports of somatic KCNJ5 mutationsin approximately 40 % of APAs, these authors reproted mutations in ATP1A1 (encodes the α-subunit of Na+/K+ ATPase) and ATP2B3 (a Ca2+ ATPase calcium channel) in much smaller proportions (5 % and 2 % respectively) of APAs. Scholl UI, Goh G, Stolting G, de Oliviera RC, Choi M, Overton JD, et al. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet. 2013;45:1050–4. This paper reported somatic mutations in CACNA1D (encodes a voltage-gated calcium channel) in 11% of APAs. Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, et al. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet. 2013;45: 1055–60. Murthy M, Xu S, Massimo G, Wolley M, Gordon RD, Stowasser M, et al. Role for germline mutations and a rare coding single nucleotide polymorphism within the KCNJ5 potassium channel in a large cohort of sporadic cases of primary aldosteronism. Hypertension. 2014;63:783–9.
