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European Journal of Endocrinology -19-0086 Background AI shouldbeinvestigatedinfuturetrials. in AIpatientsaswellapotentialroleforprovidinguseful complementaryinformationatdiagnosisandfollowup of hormone replacementtherapy,theRAASremainshyperactivated.ThecontributionofAngIIincardiovasculardiseases elevated levelsofangiotensinmetabolites,includingthepotentvasoconstrictorAngII.Despitestate-of-the-art Conclusions significantly increasedinAIpatients. 2 1 Michael Krebs Marko Poglitsch Peter Wolf in patientswithprimaryadrenalinsufficiency angiotensin–aldosterone systemfingerprint Identifying adisease-specificrenin– mineralocorticoid (MC) replacement therapy is necessary mineralocorticoid (MC)replacement therapyisnecessary glucocorticoid (GC)replacement therapy. Additionally, mineralocorticoid deficiency, requiringdaily, life-long by potentiallylife-threatening glucocorticoid and adrenal insufficiency (AI) ischaracterized Primary correlated withplasmareninactivity( AngII ratio(AA2ratio, aldosterone wasnotdetectableinthemajorityofAIpatients,resultingaprofoundlysuppressedaldosterone-to- renin concentration( Results liquid chromatographymassspectrometry. included inacross-sectionalcase–controlstudy.Angiotensinmetaboliteprofiles(RAS-fingerprints)wereperformed by healthy volunteers(female = 5;age:52 140/83 mmHg; hydrocortisonedose:21.9 Methods cardiovascular riskfactors,weperformedin-depthcharacterizationoftheRAASactivity. Since activationoftherenin–angiotensin–aldosteronesystem(RAAS)playsanimportantroleinmodulation glucocorticoid (GC)andmineralocorticoid(MC)replacementtherapy,mainlyduetoanincreasedcardiovascularrisk. Background Abstract Attoquant Diagnostics,Vienna,Austria Division ofEndocrinologyandMetabolism,DepartmentInternalMedicineIII, MedicalUniversityofViennaand https://doi.org/ https://eje.bioscientifica.com Clinical Study : InpatientssufferingfromprimaryAI,RAASactivitywashighlyincreasedwithelevatedconcentrationsof : EightpatientswithprimaryAI(female = 5;age:56 10.1530/EJE : AIisassociatedwithauniqueRAASprofilecharacterizedbytheabsenceofaldosteronedespitestrongly : Inpatientssufferingfromprimaryadrenalinsufficiency(AI)mortalityisincreaseddespiteadequate 1 , Johanna Mayr 1 2 , Alois Gessl -19-0086 P P = 0.027), angiotensin(Ang)I( = 0.003) comparedtocontrols.PRA-S,theangiotensin-basedmarkerforplasmareninactivity, 1 1 , Hannes Beiglböck © 2019EuropeanSociety ofEndocrinology 1 , Alexandra Kautzky-Willer P Wolfandothers r = 0.983; ± 21 years; BMI:25.2 ± Printed inGreatBritain 5 mg/day; fludrocortisonedose:0.061 P

< 1 , Paul Fellinger 0.01) andplasmareninconcentration( P = 0.022), AngII( ± ± 1 21 years; BMI:22.8 , Anton Luger in affectedpatientscompared togeneralpopulation, indicates amorethantwofold increaseinmortalityrates might normalizelifeexpectancy, recentevidence expectations thatregularhormone substitutiontherapy in mostaffectedpatients( 4 kg/m insufficiency RAAS activityinadrenal Published byBioscientifica Ltd. 1 , Yvonne Winhofer 2 P ; meanbloodpressure:135/84 mmHg)were = 0.032), Ang1-7and1-5.Asexpected, 1 and ±

2 kg/m ± 0.03 mg/day) andeightmatched Downloaded fromBioscientifica.com at09/29/202112:00:39PM 1 , 2 1 r ; meanbloodpressure: = 0.985; ). Incontrasttotheinitial (2019) Endocrinology European Journalof ac.at michael.krebs@meduniwien. Email to M Krebs addressed be should Correspondence 181 P 181

< :1 0.001) andwas , 39–44 ,

39 –44 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com of EndocrinologyandMetabolism. Thestudyprotocol of Vienna, DepartmentofInternalMedicineIII, Division center, case–control pilot study at the Medical University To addressour aimsweperformedacross-sectional,single- Methods order toreduceAI-associatedcardiovascularrisks. for diagnosisortherapeuticmonitoringofAIpatients in is a disease-specific RAAS profile that might be suitable AI despiteMC replacement therapy and if there primary the peptidebranchofRAASmightbestimulated in therapy. Therefore,thisstudyaimsto investigate, if treatment regimensandtoindividualizeMCsubstitution thus representapotentialclinicaladvantagetooptimize The thoroughassessmentofthestatusRAASmight increaseincardiovascularmortality( to theobserved patients sufferingfromAI( and detrimentalangiotensinmetaboliteslikeAngIIin excessive reninsecretionandelevatedlevelsofvasoactive feedback duetothelackofaldosteronemightresultin via anegativefeedbackonrenin.Animpaired in thekidneys,whichconstitutesawell-balancedsystem stimulating sodiumretentionandpotassiumexcretion results in aldosterone secretion under normal conditions, disease ( and mightcontributetothedevelopmentofcardiovascular binding toAngIItypeIreceptors(AT1R) intargettissues responsesthroughdirect and regulationofinflammatory which promotesvasoconstriction,cardiacremodeling The most prominent angiotensin metabolite is Ang II, might activelymodulatecardiovascularriskfactors. cascade with numerous angiotensin metabolites, which aldosterone system(RAAS)consistsofanenzymatic regulation ofionbalance.Therenin-angiotensin- activity, reductionofvascularcomplianceandthe myocardium bypromotionofsympatheticnervous exerts effectsonvasculature,bloodpressureandthe adrenocorticotropic hormone (ACTH)( with potassiumlevelsinthebloodandtolessextentby MC aldosteroneismainlyregulatedbyAngIItogether replacement therapy. Secretionofthemostimportant ( blood glucoseandpressure,arewellinvestigated on cardiovascular risk factors, including body weight, increased riskofcardiovasculardisease( despite consequentGCsubstitution,mainlyduetoan 3 ), onlylittleknowledge exists ontheroleofMC Clinical Study Inadequate MCreplacementtherapymightcontribute Whereas theeffectsofadistinctoversupplyGC 5 , 6 ). BindingofAngIItoadrenocorticalAT1R 7 ). P Wolfandothers 2 ). 4 ). Aldosterone 8 ). 24 treatment, bloodtestswereperformedapproximately all patientswereononcedailymorningfludrocortisone taking theirdailyGCandMCreplacementtherapy. Since morning following an overnight fast of at least 10 prior tothestudyvisit.Participantswereinvestigatedin dose ofadequate GC and MC therapyforatleast 3 months criterion forallparticipants. Patients hadtobeonstable likeperipheraledemawasanexclusion hypervolemia kidney diseaseorliveraswellclinicalsignsof included inthisstudy. ofheartfailure,chronic History healthy controlswellmatched for age,sexandBMIwere Helsinki andtheICH-GCPguidelines. and regulations,i.e.principlesoftheDeclaration conducted inconformancewiththerelevantguidelines obtained fromallparticipatingsubjects.Thisstudywas University ofVienna, and written informedconsentwas was approvedbytheethicalcommitteeofMedical signals exceededasignal-to-noise ratioof10.Equilibrium inserum matrix,onconditionthatintegrated curves response factorsdetermined inappropriatecalibration integrated chromatogramsconsidering thecorresponding sample. Analyte concentrations were calculated from across thesamplepreparationprocedureineachindividual Internal standards were used to correct for analyte recovery Milford, MA,USA)inmultiplereactionmonitoringmode. triple quadrupolemassspectrometer(Waters Xevo TQ/S, UPLC® C18,Waters) operatinginlinewitha XEVO TQ-S analysis using a reversed-phase analytical column(Acquity (LC-MS/MS) chromatotraphy tandemmassspectrometry solid-phase extraction, samples were subjected to liquid (200 labeled internalstandardsforindividualangiotensins previously ( stabilization ofconditionedplasmasamplesasdescribed measured following III, AngIV, Ang1-7and1-5aldosteronewere Vienna accordingtocurrentstandards( of theMedical University of at the central laboratory angiotensin levels)andaldosteronelevelsweremeasured fingerprint). renin, aldosteroneandangiotensinmetabolites(RAS position toassessserumelectrolytes,cortisol,ACTH, rate bloodwasdrawnafteratleast15 sampling wasabout16 from lastintakeofdailyGCreplacementtherapytoblood insufficiency RAAS activityinadrenal h afterthelastintakeofMCreplacementtherapy. Time Eight patients with primary autoimmuneAIandeight Eight patientswithprimary Equilibrium concentrationsofAngI,II, All parametersbuttheRASfingerprint(equilibrium After themeasurementofbloodpressureandheart pg) andaldosterone(500 9 , 10 ). Sampleswerespikedwithstableisotope- ex vivo h. Downloaded fromBioscientifica.com at09/29/202112:00:39PM equilibrationandsubsequent pg). FollowingC18-based 181 min ofrestinsitting www.kimcl.at :1 h before 40 ). via freeaccess European Journal of Endocrinology PRA (ngAngI/mL)/h AA2 ratio Aldosterone (pmol/L) Ang 1-5(pmol/L) Ang 1-7(pmol/L) Ang IV(pmol/L) Ang III(pmol/L) Ang II(pmol/L) Ang I(pmol/L) Renin ( quantification, dataaregivenas median (minimum–maximum);Ang,angiotensin;foraparameter withmorethan50%ofmeasuredvaluesbelowthelimit Table 2 Whitney was performedbyunpairedStudent’s on normaldistribution.Comparisonbetweengroups means statistics for Mac version 24 (IBM corp). Data are given as quantification (LLOQ). of quantification,dataweregivenas with morethan50%ofmeasuredvaluesbelowthelimit AA2 ratio,asmarkerforadrenalfunction.Foraparameter (PRA-S), angiotensin-convertingenzyme(ACE-S)andthe of angiotensin-basedmarkersforplasmareninactivity in RAAS-Triple-A evaluation,involvingthecalculation levels ofAngI,IIandaldosteronewereused dose ofmineralocorticoidreplacementtherapy. GC dose,dailydoseofglucocorticoidreplacementtherapy;MC Renin ( Aldosterone (pmol/L) ACTH (pg/mL) Cortisol ( Phosphate (mmol/L) Calcium (mmol/L) Chloride (mmol/L) Potassium (mmol/L) Sodium (mmol/L) Heart rate(bpm) Diastolic RR(mmHg) Systolic RR(mmHg) MC dose(mg/day) GC dose(mg/day) BMI (kg/m Sex (female/male) Age (years) means as adrenal insufficiencyandcontrols;dataaregiven Table 1 Clinical Study Statistical analysiswasperformedbyusingIBMSPSS μ μ ± ± IE/mL) IE/mL) standard deviationorasmedian(minimum–maximum). μ

s Baseline characteristics in patients suffering from Baseline characteristicsinpatientssufferingfrom Angiotensin metabolitesinallpatientssufferingfromadrenal insufficiency( g/dL) . 2 d ) U . orasmedian test.Correlationanalysiswasperformed 290 (85–2000) insufficiency 0.3 (0.1–3.6) 56 (14–208) 0.061 21.9 22.8 100 140 140 Adrenal 1.1 2.3 4.5 5/3 79 83 55 ± <

interquartile rangedepending 20 ± ± ± ± ± ± ± ± ± ± ± ± 0.1 0.9 1.7 0.3 1.2 16 10 16 0.03 5 3 21 < lower limitofquantification(LLOQ). P Wolfandothers 13 (6.7 174 (16–361) 9 (1.6–270) 25.2 21 (8–67) t 101 142 134 Controls -test orbyMann– 1.1 2.3 4.4 76 84 51 0.019 (0.008–0.333) < 5/3 Adrenal insufficiency ± ± ± ± ± ± ± ± ± ± 313 (15–1273) lower limitof ± < 1.5 (0.5–5.7) 6.2 ( 3.3 ( 7.4 ( 4.0 ( 20 (12–325) 57 (14–209) 0.1 0.1 2.7 0.4 2.4 14 7 13 4 21 18.5) 20 < < < < 2–22) 2.5–11.4) 2–43.6) 1.5–20.1) P 0.001 0.021 value 0.05 n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. Aldo, aldosterone;Ang,angiotensin;AP,aminopeptidase; mass spectrometry.ACE,angiotensin-convertingenzyme; angiotensin metabolites(pmol/L,medianvalue)analyzedby numbers besidethemrepresentabsoluteconcentrationsof primary adrenalinsufficiency(B).Thesizesofspheresandthe RAS fingerprintinhealthycontrols(A)andpatientswith Figure 1 endopeptidase. AT1R, angiotensin2type1receptor;NEP,neutral suffering fromAIshowedamarkedlydifferentRAS of patientswithAIandcontrols. and reninweresignificantlydifferentbetweenthegroup As expected,concentrationsofcortisol,ACTH,aldosterone and healthycontrols,whichisshownindetail electrolytes werecomparablebetweenpatientswithAI Anthropometric characteristics,bloodpressureandserum Results significance wassetat using Pearson’s correlationcoefficient.Levelofstatistical insufficiency RAAS activityinadrenal Ang 1-7 Ang 1-5 AB <2.5 <2.0

With regardtoangiotensinmetabolites patients

E AC 158.1 A Aldo

T1R T

E AC Ang I 20.2 0.695 (0.052–2.131) n Ang II < 62.8 = 8) andcontrols( 121 (54–504) 0.2 (0.1–4.9) 2.4 ( 1.9 ( 9.5 (1.6–271) 2.5 62 ( 63 (20–1218) <

2 AP Controls Ang III Ang IV < < < P 1.9 2.4 20–130) 2–33) 1.5–18.7)

< Downloaded fromBioscientifica.com at09/29/202112:00:39PM 0.05.

Ang 1-5 Ang 1-7 6.3 3.9 https://eje.bioscientifica.com n

= 8); dataaregivenas

E AC 181 :1 A <20.0

Aldo

T1R

E AC 102.6 Ang I P value n.s. n.s. n.s. n.s. 0.002 0.028 0.05 Ang II 373.9

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.

European Journal of Endocrinology https://eje.bioscientifica.com P Ang II (373 (121–1273) pmol/L vs 62 (20–336) pmol/L; I (103 (54–503) pmol/L vs 20 (12–88) pmol/L; groups showedsignificantly higherconcentrationsofAng ACE-inhibitors orAT1R blockers. Comparisonbetween more pronouncedafterexcludingallsubjects( detail in angiotensin metabolitesinthewholecohortareshown in fingerprint comparedtocontrols(see patients withAIandhealthycontrols. activity (PRA)and(B)plasmareninconcentration(PRC)in Correlation analysisofPRA-Swith(A)classicplasmarenin Figure 2

= Clinical Study 0.032), Ang1-7(3.9(2.5–11.4) pmol/Lvs Differences betweenpatientsandcontrolswereeven Table 2 . P Wolfandothers Fig. 1 ). Dataofall < n 2.5 pmol/L) 3) taking =3) P =0.022), numerous angiotensin metabolites. Whether thisislinked a characteristic,disease-specificRASfingerprintof substitution therapy. Moreover, ourdatademonstrate is markedly activated despite adequate GC and MC AI the RAAS system In patients suffering from primary Discussion ( ( I AI. with primary vs 0.2(0.1–1.4)(ngAngI/ml)/h; P markedly reduced (0.01 (0.01–0.06) vs 0.69 (0.1–1.3); AI.TheAA2ratiois patients sufferingfromprimary and Ang 1-5 (6.3 (2.4–21.7) pmol/L vs other angiotensinmetabolites suchasAng1-5andIV ( symptoms in patients suffering from chronic heart failure of Ang 1-7/Ang II is associated with worsening of clinical 1-7 isreducedinacuteheart failureandasuppressedratio might counteractleftventricularhypertrophy( 1-7 inducesvasodilatation,isanti-thrombogenicand has beneficialeffectsonthecardiovascularsystem.Ang ACE2 AngIandIIaremetabolizedto1-7,which effects. Viametabolites byexertingcounter-regulatory evidence suggestsaprotectiveroleofotherangiotensin infarction andhospitaladmission( heart failureandlowerratesofmortality, myocardial AT1R blockersarewellestablishedinthetreatmentof angiotensin-converting enzyme-1(ACE)inhibitorsand 12 from leftventricularhypertrophytoheartfailure( or fibrosis( effects oncardiomyocytes,inducingcardiachypertrophy direct andaldosterone-independentgrowth-promoting of reactiveoxygenspecies( cytokine secretion, as well by increasing the production vascular inflammationbypromotionofproinflammatory of heartfailureinmanydifferentways.AngIIinduces which is well known to play a role in the development major effective player of the classical RAAS axis is Ang II, angiotensin metabolites.Themostprominentand to beinvestigatedinfuturetrials. to thereportedincreasedriskofcardiovasculardiseasehas insufficiency RAAS activityinadrenal r r 9 +

= =0.985; =0.983; ). Preclinicalevidencealsosuggests abeneficialroleof ). Moreover, drugstargetingtheRAASsystem,mainly Ang II)stronglycorrelatedwithplasmareninactivity 0.003) andPRAissignificantlyhigher(1.8(0.6–5.7) With regardtocorrelationanalysis,PRA-S(Ang Besides theseadverseeffectsofAngII,growing RAAS representsanenzymaticcascadeofdifferent P 11 P

<

<

0.001), whichisshownin ), playinganimportantroleinthetransition

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European Journal of Endocrinology these pathophysiologicmechanisms, increasedRAAS GC exposure( inflammation afteraswitch toamorephysiological show a reduction in body weight and a decrease in systemic Studies investigatingdelayed GCreleaseformulations an inadequatecircadian rhythmmightplayarole( daily dosingofGCreplacementtherapyandtherefore disease in general population. Also an unphysiological 23 hypertension, dyslipidemiaandwaistcircumference ( hydrocortone equivalentdoseperdayareassociatedwith slightly elevated chronic exposure to morethan 20 replacement therapy, AI even since at least in secondary In partthismightbeexplainedbyoverdosingGC diseases, butalsoduetocancerandinfections( to general population, mainly because of cardiovascular show a twofold to threefold increased mortality compared AI. mortality inpatientssufferingfromprimary increased activity probably contributing totheobserved about thepotentiallyadverseeffectsofanenhancedRAAS cardiovascular riskfactors,itistemptingtospeculate investigated infuturetrials. AIhastobe of MCtherapyinpatientswithprimary the biochemicalmonitoringandtherapeuticefficacy assessment of angiotensin metabolites helps to improve with RAASinterferingantihypertensivemedication.Ifthe were evenmorepronouncedafterexclusionofsubjects 1-7 and Ang 1-5. These differences between the groups markedly elevatedconcentrationsofAngI,II, markedly increasedcomparedtomatchedcontrolswith is nointernationallyacceptedstandardreferencerange. challenges,andthere faces severalpre-analyticlaboratory Moreover, measurementofPRA,PRCandaldosterone signs offluidretentionorposturalhypotension( clinically dependingonbloodpressure,saltcraving, of therapyadequatefludrocortisonedoseisassessed of mineralocorticoiddeficiency, whereasduringthecourse aldosterone atdiagnosisofAItodeterminethepresence Clinical practiceguidelinessuggestmeasuringPRAand AI( levels ofACEinpatientswithuntreatedprimary withdrawal of fludrocortisone ( report increasedconcentrationsofAngIIandPRAafter AI under GC and MC replacement therapy. Studies of RAASactivityinpatientssufferingfromprimary II cleavage( ( 3 Clinical Study , ), whicharewell-knownriskfactorsforcardiovascular 4 Swedish registry data from retrospective cohort studies Swedish registry Since variousRAASmetabolitesmodulate In ourgroupofpatients,angiotensinmetabolitesare Up tonow, limiteddataexistonthepattern onlyvery , 5 , 6 , 7 16 , 8 ). ), whicharedownstreamproductsofAng 25 ). We hypothesize thatinadditionto 17 P Wolfandothers ), as well ashigh serum 19 mg of , 20 18 24 21 22 ). ). ). ). , profile mighthelptoguideMCreplacementtherapy. different RAASmetabolitesandadisease-specific of AngIIonthevasculature.Moreover, identificationof direct andaldosteroneindependentdetrimentaleffects beneficial inAIunderreplacementtherapybypreventing suggestthatRAASblockertherapymightbe observations effects might help to identify patients at increased risk. Our metabolites withadverseorprotectivecardiovascular needed toaddressthequestionifaratioofangiotensin to be investigated in future trials. Moreover, studies are potential cardiovascularrisksofincreasedMCactionhas RAAS activityandAngIIconcentrationsoutweighsthe normal range ( to aimforplasmareninconcentrationsintheupper which recommendstitratingdailyfludrocortisone AI.Thisisinlinewithrecentliterature, risk inprimary Ang IImightcontributetotheincreasedcardiovascular activity especially via highlyelevatedconcentrations of References related study at part taking for participants experiments. all thank authors The Acknowledgments Endocrinology andMetabolism(ÖGES)toPW. of Association Austrian the from grants by funded parts in was study This Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisstudy. no is there that declare authors The Declaration ofinterest cardiovascular mortality. are upregulatedandmightcontributetoincreased are well known to modulate cardiovascular risk factors, RAAS activity. Different angiotensin metabolites, which AI are characterized by a markedly increased from primary our study. average daily salt intake, which is another drawback of small cohort.Additionally, noadjustmentwasmadefor significant between-groupdifferenceseveninthisrather limitation ofourstudy. However, wewereabletoobserve insufficiency RAAS activityinadrenal 2 1 Bergthorsdottir R, Leonsson-Zachrisson M, Oden A&Johannsson G. Grossman AB, Johansson G,Quinkler M&Zelissen P. Therapyof Premature mortalityinpatientswith Addison’s disease: apopulation- 0450) Endocrinology insufficiency: clinicalinsightsfrom acrossEurope. endocrine disease:perspectivesonthe managementofadrenal The smallsamplesizemightbeconsideredasa In conclusion,ourdatashowthatpatientssuffering 2013 8 ). However, if the benefit of normalizing 169 R165–R175. Downloaded fromBioscientifica.com at09/29/202112:00:39PM (https://doi.org/10.1530/EJE-13- https://eje.bioscientifica.com 181 :1 European Journal of European Journal 43 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com

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6