REVIEW CPD

Primary aldosteronism: a common cause of resistant

Gregory A. Kline MD, Ally P.H. Prebtani BScPhm MD, Alexander A. Leung MD, Ernesto L. Schiffrin CM MD PhD

n Cite as: CMAJ 2017 June 5;189:E773-8. doi: 10.1503/cmaj.161486

esistant or difficult-to-control hypertension is a problem that may affect as many as 13% of all persons with hyper- KEY POINTS tension.1 It is estimated that more than 6 million (22.6%) • Difficult-to-control hypertension should trigger testing for primary Rof adults in Canada have hypertension, but less than two-thirds aldosteronism. have it adequately controlled despite conventional strategies for Measurement of -to- ratio (ARR) is the preferred 2 • treatment. Uncontrolled hypertension may arise from nonadher- diagnostic test. ence to medication, selection of suboptimal treatment regimens • Patients with high ARR who are potential candidates for surgical and/or the presence of unidentified secondary causes. It is frus- adrenalectomy and those with severe hypertension for whom trating for both the patient and treating physician. Patients may discontinuation of antihypertensive drugs would be dangerous embark upon a series of variably successful approaches with dif- should be referred to a hypertension specialist for assessment. ferent drug classes. We review the accumulating epidemiologic • Patients with very severe hypertension who may not tolerate drug evidence on and hypertension that is adjustment for ARR measures should also be assessed by a hypertension specialist. resistant to treatment. We offer a pragmatic approach to diagno- sis for generalist physicians. Although no randomized controlled • Patients who cannot be considered for adrenalectomy may consider an empiric trial of or for blood pressure control. trials (RCTs) have reported a mortality benefit to screening or If a normal or negative result for ARR testing is reported yet clinical treatment for primary aldosteronism, multiple case-control, • suspicion of primary aldosteronism is high, repeating the test is registry-based and systematic reviews of existing data may be appropriate after the patient has stopped taking all - used to construct a coherent, evidence-informed approach to converting-enzyme-inhibitors, angiotensin receptor blockers, diagnosis and treatment (Box 1). Detection of primary aldosteron- dihydropyridine calcium-channel blockers and/or diuretics for at ism may allow disease-specific treatment that could improve least two weeks, to maximize test sensitivity; use of α-blockers or non-dihydropyridine calcium-channel blockers may be necessary to rates of blood pressure control3 and may reduce the morbidity control blood pressure in the interim. associated with resistant hypertension.4

What is primary aldosteronism? description, it was quickly recognized that primary inappropriate Primary aldosteronism (called Conn syndrome for many years aldosterone hypersecretion could be due to either an adrenal afterJerome Conn who first described it in 19555) refers to the mass or bilateral hyperplasia of the adrenals. presence of a benign adrenocortical mass secreting aldosterone Aldosterone is a salt-retaining secreted by the zona in a relatively autonomous fashion, often causing severe hyper- glomerulosa layer of the . It is secreted primarily tension and . In the years that followed the original in response to the effect of renin via angiotensin II, although pituitary-derived adrenocorticotropin hormone has a smaller, secondary stimulatory effect, as does an elevated serum potas- Box 1: Evidence used in this review sium concentration. Aldosterone facilitates resorption, and and hydrogen secretion at the principal cells of We searched MEDLINE databases using combinations of the terms “aldosteronism,” “resistant hypertension,” “refractory the distal tubule and collecting duct. Resorption of sodium is hypertension,” “prevalence,” “review” and “guidelines.” This considered to be the primary mechanism for an associated rise search yielded numerous citations from within the past 15 years. in blood pressure observed with activation of the mineralocorti- We focused on the most recent publications, systematic reviews, coid receptor. Aldosterone also exerts effects on blood vessels, guideline statements and highly cited articles. We focused on leading to remodelling, fibrosis and endothelial dysfunction, articles that included the largest numbers of patients, those that were conducted in a primary care setting and pertinent guidelines and on the heart, inducing cardiac fibrosis and hypertrophy. (e.g., from the Endocrine Society and Hypertension Canada). It has been shown that hypokalemia (the traditional clue to the diagnosis of aldosteronism) is only present in less than 20%

© 2017 Joule Inc. or its licensors CMAJ | JUNE 5, 2017 | VOLUME 189 | ISSUE 22 E773 REVIEW logic processesinvolved.Theseincludeeithersomatic patients whowerenewlydiagnosedwithhypertension. ment in Sweden reported a prevalence of 5.5% among 200 ing studyforprimaryaldosteronisminacareenviron- thesis andsecretion, dent adipose–cell-secretedligandthatdrivesaldosteronesyn- evidence hassuggestedthatthereisapossibilityofanindepen- patients presentinadulthood. lation of a single prevalence point estimate. referral centresweretooheterogeneousinnaturetoallowcalcu- aldosteronism of3%to13%inprimarycareand1%30% 42 000 patientsconcludedthatreportsofprevalenceforprimary recently publishedsystematicreviewofstudiesinvolvingover chemical definitionofprimaryaldosteronismbetweencentres.A interpretation ofthesereportsislimitedbydifferencesinthebio- more frequentdiagnosticconsiderationinprimarycare(Box 2). enough andhassufficientlyspecifictreatmentoptionstojustify consistent messageisthatprimaryaldosteronismcommon 10% to20%, resistant hypertension,primaryaldosteronismmaybepresentin tension thanpreviouslythought.Amongpatientcohortswith is moreprevalentinmodernpopulationsofpatientswithhyper- representing afullspectrumofethnicdiversity. lence forprimaryaldosteronismnowavailablefromcountries increased susceptibility,withbroadlysimilarreportsofpreva- E774 95% CI3.2–45.2). OR 12.1, 95%CI1.5–27.4;foratrial fibrillation: :OR 6.5, odds ratio[OR]4.2,95%confidence interval[CI]2.0–8.6;fornonfatal , nonfatalmyocardialinfarction oratrialfibrillation(forstroke: patients withprimaryaldosteronism hadincreasedoddsofhavinga pressure with 465 patients with essential hypertension, found that who werematchedforage,gender,andsystolicdiastolicblood diagnosed withprimaryaldosteronismduringathree-yearperiod, case–control studyconductedinFrancethatinvolved124patients ative healthoutcomesthanpatientswithessentialhypertension. A patients withprimaryaldosteronismexperiencehigherratesofneg - Evidence from case–control and registry studies suggests that aldosteronism? Why isitimportanttodiagnoseprimary ism fromfivecontinents A 2004reviewofestimatesprevalenceprimaryaldosteron- How commonisprimaryaldosteronism? of cases; obesity-related resistanthypertensionandaldosteroneexcess. may be seenin a pediatric or adolescent patient line primary care)theprevalence is reported at 1%to6%. with mildtomoderatehypertension(e.g.,asmaybetypicalof nels, andectopichormonereceptors. cause. In primary aldosteronism, there are many potential patho As yet, there are no specific geographic or racial markers of 10 mutations in the genes for adrenocortical potassium chan- 7 Veryuncommonfamilialformsofprimaryaldosteronism 6 morelikelywithanunderlyingadrenaladenomaasthe 15,16 andamongless-selectedpopulationsofpatients 12 potentiallyexplainingthelinkbetween 14 concludedthatprimaryaldosteronism 26

A retrospective study of 270 patients A retrospective study of270 patients 11 Somerecentcompelling CMAJ 21 Nonetheless, the | 14,19,20 JUNE5, 2017 8 17 but most However, 9 18 Ascreen- orgerm-

13 - | VOLUME 189 high saltintake)appearstoleadvascularsmoothmuscleprolif- ney. mineralocorticoid receptorsontheheart,bloodvesselsandkid- inappropriate elevationofcirculatingaldosteroneactingthrough in patientswithprimaryaldosteronismoccurbecauseeffectsof high risk ofcardiovascular disease. Cardiovascular complications suggesting aco-associationoftwoconditionsalreadylinkedwith development oftype2diabetes hypertrophy, linked primaryaldosteronismtoahigherriskofleftventricular patients, patients withprimaryaldosteronismcomparednormokalemic complications, in particular, were more common in hypokalemic patients insixcentresGermanyreportedthatcardiovascular 95% CI 1.4–2.8). 95% CI with 12.7%amongthoseessentialhypertension(OR 2.0, 22.6% amongthepatientswithprimaryaldosteronismcompared events over12yearsreportedatotalcardiovasculareventrateof essential hypertensionandfollowedforhypertension-related with with primaryaldosteronismmatched1:3810 patients disease-specific therapyisinstituted. filtration renal injury mary aldosteronismmayportendaworseprognosis. than aprevalenceof9%inthosewithoutprimaryaldosteronism, apnea inpatientswithprimaryaldosteronism,significantlyhigher Southern Californiadatabasereportedan18%prevalenceofsleep pared withessentialhypertension.Astudyof3428patientsina Strauch et al. Abdelhamid et al. Milliez et al. Yin et al. Fogari et al. †Extremely restrictive aldosteronism. definitionofprimary *Minimum of300participants. Loh Ket al. Unselected/primary care hypertension Setting setting* andcountry aldosteronism, determined prospectively, by patient Box 2:Studies reporting prevalence of primary Matrozova et al. Stowasser et al. Lim et al. Rossi et al. Referred to specialtyhypertension clinic/resistant hypertension Omura et al. Primary aldosteronismappearstobeassociatedwithahyper- 38,39 The detrimental effect of aldosterone excess (along with Thedetrimentaleffectofaldosteroneexcess(alongwith 29 25 22 whichsuggeststhatthepresenceofhypokalemiainpri- 6 19 | 17 ISSUE 22 26 20 32 15 enhancedvascularstiffness, 24 27 28 23 A retrospective cross-sectional study involving Aretrospectivecross-sectionalstudyinvolving 30 that may not be fully appreciated until after that may not be fully appreciated until after patients No. of 5438 3900 1125 1020 3000 402 376 313 300 465 350 35 andpoorerqualityoflife Republic Czech Bulgaria China Australia UK Singapore France Germany Italy Japan Italy which study Country in Country conducted 31 was Smaller studies have also Smallerstudieshavealso 33 vasculardissection, aldosteronism, prevalence of Reported primary primary 12.5 11.2 2.3† 6.9 9.2 6.6 6.0 5.9 19 18 % 5 36 com- 37 34

REVIEW - E775 Prescrip- 44 Proceeding with further Proceeding with further 7 35 26 consultation with an expert in consultation with an expert in Box 4 provides suggested ARR ARR suggested provides 4 Box 33,34 44 32 45 37 30 36 26 which are features strongly predictive of aldo- which are features strongly predictive of 30 52,53 ISSUE 22 ISSUE 26 | blockers or non-dihydropyridine calcium-channel block- blockers or non-dihydropyridine calcium-channel - Albuminuria Chronic disease Left ventricular hypertrophy Vascular stiffness, dissection Metabolic syndrome/type 2 diabetes Obstructive sleep apnea Anxiety/depression Stroke Nonfatal myocardial infarction Atrial fibrillation • • • • • • • Box 3: Increased risk of complications associated with primary aldosteronism compared with essential hypertension • • • Like most endocrine tests, the numeric determination of what of determination the numeric tests, endocrine Like most ers may be necessary to control blood pressure in the interim. ers may be necessary to control blood pressure sterone-producing adrenal . constitutes a normal versus abnormal result for an ARR test is ARR test is result for an a normal versus abnormal constitutes and specific- acceptable sensitivity between often a compromise test cut- and any given numerical disease in question, ity for the is reported upon the way the test to some extent off will depend laboratory. individual an by hypertension should be considered because confirmatory testing hypertension should be considered because to interpret. However, can be challenging to perform and difficult for highly probable confirmatory testing may be unnecessary extremely or hypokalemia spontaneous with those as such cases, elevated ARRs, interpretation levels that take local laboratory methodology into that take local laboratory methodology into interpretation levels a an indication of what may be considered account, along with “strongly positive” test result. Discussion “weakly positive” or determine to necessary be may director laboratory local the with If setting. practitioner’s the to applicable most be line will which result for ARR testing is reported yet clinicala “normal or negative” is test the repeating high, is aldosteronism primary of suspicion patient has stopped taking all angiotensin- appropriate after the inhibitors, angiotensin receptor blockers,converting-enzyme (ACE) at blockers and/or diuretics for dihydropyridine calcium-channel least two weeks, of the test. to maximize the sensitivity After a positive ARR test result, biochemical confirmatory testing confirmatory biochemical result, test ARR positive a After is frequently recommended; What should be done for patients with a high What should be done for patients result for ARR testing? ence, feasibility of surgery and availability of specialized endo- ence, feasibility of surgery and availability test- confirmatory biochemical is there once facilities testing crine adrenal unilateral with patients In aldosteronism. primary of ing In patients unwilling ordisease, adrenalectomy may be curative. bilateral adrenal hyper- unable to undergo surgery, or those with antagonist such as spi- plasia, empiric therapy with an aldosterone ronolactone or eplerenone should be considered. localization investigations should be guided by patient prefer patient by guided be should investigations localization tion of α VOLUME 189 VOLUME |

51 44 47,48 JUNE 5, 2017 | CMAJ the cumulative evidence of addi- the cumulative evidence 42,43 At minimum, to avoid false-negative At minimum, to avoid false-negative 49,50 40,41 Testing is particularly useful for patients who who Testing is particularly useful for patients

46 Many studies of primary aldosteronism and associated clinical and associated of primary aldosteronism Many studies outcomes are potentially confounded by their retrospective by their retrospective confounded are potentially outcomes risk mark- cardiovascular bias and use of surrogate design, referral is resistant hypertension given that undifferentiated ers. However, associated with a high degree of morbidityalready known to be death, and excess premature

Most patients being screened for primary aldosteronism will Most patients being screened for primary aldosteronism will continues Debate drugs. antihypertensive taking be already about the exact role and importance of avoiding drug interfer- ence in ARR testing. What are the important considerations for ARR testing? The guideline from Hypertension Canada recommends targeted recommends Canada Hypertension from guideline The of pri- suggestive testing for hypertensive patients with features (Box 4) aldosteronism mary evidence level grade-D on based (consensus). Who should be considered for testing? Who should be considered for The hallmark of primary aldosteronism is elevated levels of plasmaThe hallmark of primary - with low levels of renin. Normally, the pro aldosterone combined to leads apparatus juxtaglomerular renal the by renin of duction the generation of angiotensin I converted to angioten- that is then synthesis and secre- sin II, which eventually stimulates aldosterone and inappropri- tion. When aldosterone is produced autonomously negative feedback ately by one or both adrenal glands, normal high-aldosterone/low- leads to profound suppression of renin. This plasma aldosterone-to- renin state is best captured by measuring the first clue, especially in A high ARR is typically (ARR). ratio renin of primary aldoste- the normokalemic patient, to the presence the preferred test. ronism and is currently recommended as How is primary aldosteronism diagnosed? How is primary eration and fibrosis, along with impaired vascular-endothelial vascular-endothelial with impaired along and fibrosis, eration function. vasodilatory tive health risks of excess aldosterone plus resistant hypertensiontive health risks of excess - for early consideration of testing for pri supports a strong case - patients with difficult-to-control hyperten mary aldosteronism in complications (Box 3). sion or early cardiovascular results for the test, patients must refrain from taking spironolac- tone for at least four to six weeks prior and supplemented with potassium (taken orally) if hypokalemic. Ideally, patients should follow an ad lib or high-salt diet for two days before testing; patients may need specific instruction because many will have have will many because instruction specific need may patients Blood samplesintake. to limit sodium previously counselled been should be taken with the patient seated and before 10:00 am, although fasting is not required. would be potential candidates for adrenalectomy if a unilateral if a unilateral would be potential candidates for adrenalectomy Patients who are adrenal aldosteronoma were to be found. may not require already known to be poor surgical candidates with mineralocorti- extensive investigation. Empiric treatment coid receptor antagonists (such as spironolactone or eplere- none) may be considered as a preferred alternative. REVIEW receptor blockers. dispose tohyperkalemia,suchasACEinhibitorsorangiotensin taking 25 mg perday, taking 25 mg occursinasmany10%ofoldermenwhoare available. Antiandrogenactivityleadingtosymptomssuchas (removing aldosteroneexcess)ormedicaltreatment(blocking spective studiesareneededtodeterminewhethersurgical ARR < 40 mL/min/m with renalimpairment(estimatedglomerularfiltrationrateof gested towatchforhyperkalemia,particularlyinthosepatients apy, monitoringofserumcreatinineandelectrolytelevelsissug- age withoutcontraception.Afterstartingspironolactonether- , itshouldnotbeofferedtowomenofchild-bearing 1685) were able to achieve drug-free normotension. ism reported that 52% (95% CI 44%–60%) of these patients (n = ectomy thatexaminedsurgicaloutcomesforprimaryaldosteron- meta-analysis ofstudiesinvolvingpatientsundergoingadrenal- regression ofcomplicationsfromprimaryaldosteronism. spective studiessuggestsequalefficacyinthepreventionor E776 geted medicaltreatment, achieve bloodpressurecontrolfollowingeithersurgeryortar- present andlesspotent. blood pressureinthosewithprimaryaldosteronism, shown repeatedlythatthisagentishighlyeffectiveatcontrolling trial foressentialhypertension,butclinicalexperiencehas drug, ithasneverbeenstudied in alargeprospective controlled is apotentblockerofthemineralocorticoidreceptor.Asanolder comastia; pensity toblocktheandrogenreceptorandthuscauselessgyne- As manyas97%ofpatientswithprimaryaldosteronism may Spironolactone has been in clinical use for over 50 years and Spironolactone hasbeeninclinicaluseforover50 years 48,55 andresistanthypertension. 59 however,itismoreexpensivethanspironolactoneat 2 ) 57 58 orthosewhoaretakingotherdrugsthatpre- Eplerenoneisnewerandhasmuchlesspro- 56 Renin concentration (ng/L) Renin concentration (mU/L) Plasma renin activity (ng/mL/h) Method for measuring renin Interpretation of aldosterone-to-renin ratio* • • • • How to request testing for aldosterone-to-renin ratio • • • • Indications for testing for aldosteronism primary recommended by Hypertension Canada Box 4:Approach to investigating suspected aldosteronism primary aldosterone inpmol/Lisassumed. *Dependent uponthemethod for renin measurement usedby thelocal laboratory; however, standard reporting of Note: ARR=aldosterone-to-renin ratio. withhigherratesatlargerdosages.Asan while thepatient isseated andpriorto 10:00am(fasting isnot required). ofaldosteronePlasma levels andrenin shouldberequested, withsamplecollection occurring If hypokalemic, thepatient shouldreceive oral potassium replacement to restore eukalemia. Patient shouldbe instructed to follow ahigh-saltdiet for two days priorto testing. Patient shouldstop taking spironolactone oreplerenone for four to six weeks priorto testing. Hypertension withknown adrenal mass Spontaneous hypokalemia withhypertension (< 3.5 mmol/L) Hypertension withhypokalemia induced by diuretics useofthiazide/thiazide-like (< 3.0 mmol/L) diureticthiazide/thiazide-like Uncontrolled hypertension despite (> 140/90 mmHg) useofthree drugs,oneofwhichisa 60 andevidencefromtwosmallpro- 45 Itisinexpensiveandwidely CMAJ | JUNE5, 2017 3 Further pro- 54 Weak positive result for ARR elevated 61,62 A 100–144 550–750 60–90 44 | VOLUME 189 and tissueconsequencesofthisdisease. aldosterone excess)issuperiorforamelioratingthehypertensive aldosteronism. which appearstobeirreversibleevenaftercorrectionofprimary renal injury that is uncovered by treatment following diagnosis, patients withprimaryaldosteronismhavesubstantialchronic treatment forprimaryaldosteronismhaveindicatedthatmany hypertension. Prospective studies involvingpatients undergoing primary aldosteronismfrequentlyfollowsalengthyhistoryof mon causeofresistanthypertensionworldwide.Adiagnosis Primary aldosteronismhasbeenshowntobeaseriousandcom- for primaryaldosteronism? What istheroleofprimarycareincasefinding with uncontrolledbloodpressure,itmayplayatissue-specific cause of resistant hypertension worldwide. Beyond its relation Primary aldosteronism is now known to be a relatively common Conclusion pave thewayforindividualizeddisease-specifictreatment. many difficult-to-treatcasesofresistanthypertensionandwill mary aldosteronismwillallowphysiciansto“putaname”on However,fornow,recognitionofadiagnosispri- (see Box 5). routine careareneedednow.Someclinicalquestionsremain cal incorporation of diagnostics for primary aldosteronism in unlikely to be conducted; therefore, recommendations for practi- screening for primary aldosteronism versus no screening are the initialdiagnostictest.Randomizedcontrolledtrialsof tion ofpatientsforprimaryaldosteronismtestinginconducting primary carepractitionerstobecomemoreinvolvedintheselec- 45 | ISSUE 22 Strong positive result for ARR 31,63 This evidence points to an important role for > 144 > 750 > 90 46 REVIEW

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44. 43. 45. 46. 36. 37. 38. 39. 40. 41. 42. 33. 34. 35. 29. 30. 31. 32. 28. 24. 25. 26. 27. 19. 20. 21. 22. 23. 18. VOLUME 189 VOLUME | ​ JUNE 5, 2017 | CMAJ - www.transla Available: Transl Res 1955;45:3–17. Best Pract Res Clin Endocrinol Metab 2015;29:633–45. Does a strategy of aldosterone antagonism improve morbidityDoes a strategy of aldosterone patients compared with presentor mortality in hypertensive treatments? What is the most cost-effective approach to the investigation of to the investigation cost-effective approach What is the most Canada? primary aldosteronism in warrant consideration of aWhat other clinical scenarios (e.g., obstructive sleepdiagnosis of primary aldosteronism apnea)? Does more aggressive or standardized screening for primary or standardized Does more aggressive pressure control among improve rates of blood aldosteronim resistant hypertension? patients with Benham JL, Eldoma M, Khokhar B, et al. Proportion of patients with hypertensionBenham JL, Eldoma M, Khokhar B, et al. Proportion of patients a systematic resolution following adrenalectomy for primary aldosteronism: review and meta-analysis. J Clin Hypertens (Greenwich) 2016;18:1205-12. of arterial hypertension Rossi GP, Cesari M, Cuspidi C, et al. Long-term control of primary aldo- and regression of left ventricular hypertrophy with treatment steronism. Hypertension 2013;62:62-9. address. Presidential JW. Conn 2016 Dec. 13).tionalres.com/article/0022214355900482/fulltext (accessed of prevalence study of the C, et al. A prospective G, Caliumi GP, Bernini Rossi J Am Coll Cardiol 2006; primary aldosteronism in 1125 hypertensive patients. Padwal RS, Bienek A, McAlister FA, et al. Epidemiology of hypertension in Canada:Padwal RS, Bienek A, McAlister FA, et al. Epidemiology of an update. Can J Cardiol 2016;32:687–94. Fogari R, Preti P, Zoppi A, et al. Prevalence of primary aldosteronism among aldo- an of the use on based study prospective a patients: hypertensive unselected sterone/renin ratio above 25 as a screening test. Hypertens Res 2007;30:111-7. Persell SD. Prevalence of resistant hypertension in the , 2003– Persell SD. Prevalence of resistant hypertension in 2008. Hypertension 2011;57:1076-80. 48:2293-300. score to diagnose Küpers EM, Amar L, Raynaud A, et al. A clinical prediction 2012;97:3530-7. unilateral primary aldosteronism. J Clin Endocrinol Metab of mineralocorticoidZennaro MC, Boulkroun S, Fernandes-Rosa F. Inherited forms hypertension. Lenzini L, Rossitto G, Maiolino G, et al. A meta-analysis of somatic KCNJ5 K + channel mutations in 1636 patients with an aldosterone-producing adenoma. J Clin Endocrinol Metab 2015;100:E1089-95. Murthy M, Xu S, Massimo G, et al. Role for germline mutations and a rare coding sin- gle nucleotide polymorphism within the KCNJ5 potassium channel in a large cohort of sporadic cases of primary aldosteronism. Hypertension 2014;63:783-9. Mazzuco TL, Grunenwald S, Lampron A, et al. Aberrant hormone receptors in primary aldosteronism. Horm Metab Res 2010;42:416-23. Ehrhart-Bornstein M, Lamounier-Zepter V, Schraven A, et al. Human adipocytes secrete mineralocorticoid-releasing factors. Proc Natl Acad Sci U S A 2003;​100:14211-6. Calhoun DA, Sharma K. The role of aldosteronism in causing obesity-related cardiovascular risk. Cardiol Clin 2010;28:517-27. Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldoste- ronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 2004;89:1045-50. hyperaldosteron- of primary Prevalence et al. Hampf M, B, Zelinka T, Strauch ism in moderate to severe hypertension in the Central Europe region. J Hum Hypertens 2003;17:349-52. among black Calhoun DA, Nishizaka MK, Zaman MA, et al. Hyperaldosteronism and white subjects with resistant hypertension. Hypertension 2002;40:892-6. • • • Box 5: Unanswered questions Box 5: Unanswered •

4. 6. 1. 7. 9. 3. 2. 5. 8.

References 10. 11. 12. 13. 14. 15. 16. 17. - cardiovascular consequences that accom role in the adverse - For patients with a diagnosis of pri pany resistant hypertension. - disease-specific treatment is widely avail mary aldosteronism, of blood pressure. able, inexpensive and effective for control aldosteronism can Measurement of ARR for diagnosis of primary tool in primary and be readily implemented and is a highly useful and treatment specialty care to facilitate the detection, diagnosis of this potentially remediable condition. REVIEW 51. 50. 49. 48. 47. 54. 53. 52. E778

reviewed. This articlewassolicitedandhas other competinginterestsweredeclared. tant andlecturefeesfromNovartisUS.No lecture fees from Servier Canada, and consul- search andServierFrance.Hehasreceived from theCanadianInstitutesofHealthRe- lines. Ernesto Schiffrin has received grants Hypertension Canada,ClinicalPracticeGuide- Servier andistheChair,EndocrineSection, ceived consultantandspeakerfeesfrom Competing interests:

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